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Neurosignals 2012;20:164–185
DOI: 10.1159/000334489
Neurons on the Move: Migration and
Lamination of Cortical Interneurons
Clare Faux a Sonja Rakic c William Andrews c Joanne M. Britto a, b
a Centre for Neuroscience, University of Melbourne, and
b Howard Florey Institute, Florey Neuroscience Institutes,
Parkville, Vic. , Australia;
c Department of Cell and Developmental Biology, University College London, London , UK
genitors found in human and non-human primates and il-
lustrate how the disruption of early developmental events
can instigate a loss in GABAergic function.
Copyr ight © 2012 S. Karger AG, Ba sel
Introduction
The neocortex is the part of the brain involved in high-
level cognitive functions, and its expansion is regarded as
a major evolutionary modification that led to the emer-
gence of intelligence
[1, 2] . These processes are achieved
through the cellular balance between neuronal excitation
and inhibition within cortical circuits. The pyramidal
neurons act primarily through the axonal release of the
neurotransmitter glutamate to excite cortical and non-
cortical targets. In contrast, the majority of inhibitory
neurons (interneurons) project locally to arborize in the
same or multiple cortical columns
[3, 4] , and a small
number can extend long-range projections into remote
cortical areas
[5] . This highly diverse neuronal popula-
tion modulates the output of excitatory pyramidal activ-
ity through the actions of the inhibitory neurotransmit-
ter, ␥ -aminobutyric acid (GABA). Throughout embryon-
ic and postnatal stages, GABA signalling is also required
for cell migration, axonal and dendritic remodelling and
Key Words
Interneuron ⴢ Cortical plate ⴢ Subtype specification ⴢ
Migration ⴢ Lamination
Abstract
The modulation of cortical activity by GABAergic interneu-
rons is required for normal brain function and is achieved
through the immense level of heterogeneity within this neu-
ronal population. Cortical interneurons share a common or-
igin in the ventral telencephalon, yet during the maturation
process diverse subtypes are generated that form the char-
acteristic laminar arrangement observed in the adult brain.
The long distance tangential and short-range radial migra-
tion into the cortical plate is regulated by a combination of
intrinsic and extrinsic signalling mechanisms, and a great
deal of progress has been made to understand these devel-
opmental events. In this review, we will summarize current
findings regarding the molecular control of subtype specifi-
cation and provide a detailed account of the migratory cues
influencing interneuron migration and lamination. Further-
more, a dysfunctional GABAergic system is associated with a
number of neurological and psychiatric conditions, and
some of these may have a developmental aetiology with al-
terations in interneuron generation and migration. We will
discuss the notion of additional sources of interneuron pro-
Publish ed online: May 4, 2012
Joanne Britto
Florey Neuroscience Institutes
University of Melbourne
Parkv ille, Melbourne, VIC 3010 (Australia)
Tel. +61 3 9035 6586 E-Ma il joanne.britto
@ florey.edu.au
© 2012 S. Ka rger AG, Basel
1424–862X/12/0203–0164$38.00/0
Accessible online at:
www.karger.com/nsg
Migration and Lamination of Cortical
Interneurons
Neurosignals 2012;20:164–185
165
synapse formation [6] ; thus, interneurons are key modu-
lators of cortical development and plasticity, in addition
to playing a crucial role in shaping the spatiotemporal
pattern of neuronal activity.
The last few years have seen an explosion in publica-
tions surrounding interneuron development. The diver-
sity of subtypes based on morphological, molecular and
electrophysiological differences accentuates the highly
specialized role these neurons play in cortical circuits.
More recently, we have started to recognize the implica-
tions of a dysfunctional GABAergic system in neurode-
velopmental disorders, and our efforts go towards ad-
dressing the underlying causes of such disturbances in
cortical function. As mentioned, the fu nctional heteroge-
neit y of interneuron s is key in modulat ing corti cal circu it
activity, and a number of recent reviews have discussed
how this diversity is associated with cortical function
[7–
9] . In this review, we will focus on how interneurons are
reliant on intrinsic and extrinsic cues during embryogen-
esis to establish subtype specification and discuss the
impact of these cues on migration and lamination. Fur-
thermore, we will discuss the latest findings of interneu-
ron generation during human cortical development, as
knowledge in these mechanisms has long-term implica-
tions in defining the aetiology of many neurological and
psychiatric conditions.
Cortical Interneuron Origin
Cortical Interneuron Origin in Rodents
The concept that pyramidal neurons and interneurons
arise from distinct progenitors and display different mi-
gratory routes was illustrated by a number of key studies
performed in rodents. Initially the use of recombinant
retroviral labelling identified clones of cells composed
solely of either pyramidal or non-pyramidal cells
[10 , 11]
suggesting the existence of separate progenitor pools for
these two cell types. Similar studies drew attention to the
appearance of tangentially migrating neurons through-
out the intermediate zone (IZ), demonstrating the wide-
spread and unorthodox dispersion of these cells within
the cortex
[12–15] . Although it was not clear at the time
that these tangentially migrating neurons originated in
the ventral telencephalon, a subsequent series of elegant
experiments placing DiI crystals in the ventral telenceph-
alon demonstrated the migration of the cells into the neo-
cortex, a phenomenon that was blocked by an incision
made between the dorsal (pallium) and ventral (subpal-
lium) telencephalon
[16 –19] . It therefore appears that the
majority of interneurons are derived from an extracorti-
cal source, the ganglionic eminences (GEs) of the ventral
telencephalon. There is however evidence to suggest that
the dorsal telencephalon can provide a local source in the
rodent cortex [11, 20] , and this may also be the case in hu-
man and non-human primates. These aspects of inter-
neuron origin will be discussed in more detail below.
In the mouse, the GEs in the ventral telencephalon ap-
pear around embryonic (E) day 11 and can be structur-
ally divided into 3 separate areas, lateral (LGE), medial
(MGE) and caudal (CGE), depending on the rostrocaudal
and mediolateral position ( fig.1 ). Utilizing DiI labelling
of individual GEs, and in vivo transplantation studies, it
was confirmed that almost all cortical interneurons are
produced within the MGE and CGE
[16 , 17, 21–24] . The
genetic link for GE involvement in the genesis of inter-
neurons was found by analyzing knockouts of the ho-
meobox-containing transcription factors expressed in
this region, namely, Dlx1, Dlx2 and Nkx2.1. Dlx1 and
Dlx2 are highly expressed in the GE and the double
knockout showed a 70% reduction in the number of cor-
tical interneurons
[19] . In comparison, Nkx2.1 is ex-
pressed solely in the MGE, and the knockout exhibits
only a 50% decrease in interneuron numbers
[25, 26] .
More recently, the contribution of interneurons from the
CGE has been examined by genetic fate mapping studies
indicating that approximately 30% of cortical interneu-
rons are produced within this area
[27, 28] .
The involvement of the LGE in generating cortical in-
terneurons has been more controversial. Numerous in vi-
tro and in vivo studies have shown that LGE-derived cells
fail to migrate to the dorsal cortex
[16, 21, 23, 29] ; how-
ever, others have shown the presence of bromodeoxyuri-
dine-labelled LGE cells in the cortex after heterotopic
transplantation
[30, 31] , and tangentially migrating cells
were present in the rat cortex following ablation of the
MGE
[32] . One caveat for these experiments is that the
migratory route of MGE- and CGE-derived interneurons
is through the LGE. Nonetheless, we cannot completely
rule out the LGE as a potential source of cortical neurons.
In addition to the GE, a small percentage of cortical in-
terneurons are derived from the embryonic pre-optic
area
[33] . Genetic lineage tracing using the transcription
factor Nkx5.1 and in utero labelling to specifically label
the pre-optic area has shown that GABAergic cells from
this region also migrate to the cortex and hippocampus.
The studies mentioned above indicate that the major-
ity of interneurons are derived from the MGE and CGE
and undergo their final mitosis in these regions prior to
migration. However, proliferating interneuron progeni-
Faux /Rakic /Andrew s /Britto
Neurosignals 2012;20:164–185
166
tors have been observed in the postnatal subventricular
zone (SVZ)
[11, 20, 30] and the IZ [20] of the cortex. Wu
et al.
[20] determined that these cells originated in the
GE, and maintained the ability to proliferate after reach-
ing the cortex to produce GABAergic daughter cells. A
separate study has identified a pool of proliferating
GABAergic precursor cells in the postnatal dorsal white
matter
[34] , and although the authors infer the origin of
these cells is the LGE/CGE, this is yet to be determined.
The requirement for these proliferating GABAergic in-
termediate progenitors in the cortex remains unknown;
however, they may provide a source of inhibitory cells
during the late stages of cortical maturation.
Interneuron Origin in Human and Non-Human
Primates
The ability to conduct in vitro and in vivo manipula-
tions, as well as access to transgenic and fate mapping
technologies, has made rodents a pertinent model to ad-
vance our understanding of cortical development. None-
theless, if we compare across species, there is an obvious
evolutionary increase in the number of both pyramidal
neurons and interneurons found in the cortex of higher
primates. This is evident by the increase in proportion of
GABAergic neurons from 15% in rodents to 25% in the
monkey and reaching 34–44% in certain supragranular
layers in the macaque and human
[35] . In addition, the
existence of interneurons displaying widely varying mor-
phologies in primates indicates that not only are more
interneurons required, but newer forms have also been
generated. The double bouquet cell originally described
in the human cortex by Ramon y Cajal in 1899 and later
rediscovered in primates
[36] is an archetypal example of
this variation. Thus, the question can be raised of wheth-
er developmental mechanisms have evolved an addition-
al source of progenitors to proportionately balance the
increase in excitatory neurons in a more complex brain.
A hint that this may indeed be the case for human and
non-human primates was discovered by Letinic et al.
[37]
in 2002. This study identified cells in the ventricular zone
(VZ) and SVZ of the dorsal telencephalon at mid-gesta-
tion, which co-expressed GABA with the GE-associated
transcription factors Mash1 (ASCL) and Dlx1/2. In ro-
dents, these transcription factors are associated with in-
terneuron generation
[38, 39] , and although Mash1 is
expressed by progenitors in the GE, it is normally un-
detectable in postmitotic migratory interneurons. The
proliferative capacity of these novel GABA/Mash1-posi-
b
c
a
bc
Fig. 1. Schematic representation of migra-
tory routes ut ilized by interneurons gener-
ated in the GEs.
a Cortical interneurons
born in the MGE and CGE in the ventral
telencephalon follow tangential migratory
paths into the developing cortex. Once
within the cortical wall, cells disperse be-
fore entering the cortical plate and reside
in a final position. The LGE-derived neu-
rons migrate rostrally and ventrally into
the olfactory bulb (OB) and striatum, re-
spectively.
b Coronal section (indicated in
a ) illustrating the major routes of tangen-
tial migration through the embryonic tel-
encephalon. Interneurons migrate from
the MGE (M) and traverse the LGE (L)
whilst avoiding the striatum (Str). Upon
entry into t he cortical wa ll, cells migr ate in
3 major streams, through the marginal
zone at early stages, followed by a second
route in the intermediate zone and at later
stages th rough the subplate.
c Intracortical
migration represented as multidirectional
migration within the marginal zone (indi-
cated in
b ), the inward and outward radial
migration from the tangential paths into
the cortical plate and the ventricle-direct-
ed migr ation towards the ventricu lar zone.
Migration and Lamination of Cortical
Interneurons
Neurosignals 2012;20:164–185
167
tive cells was tested using retroviral labelling in organo-
typic cultures and a clonal analysis revealed expression of
GABA and Dlx2 in the migrating cells a nd Mash1 expres-
sion in both the dividing progenitors and migrating cells
[37] . This study highlighted for the first time a local cor-
tical origin of GABAergic interneurons capable of gener-
ating the majority of interneurons; however, these results
are not without controversy. It is possible that the Mash1-
positive progenitors are a form of migrating intermediate
progenitor/amplifier cell originating in the GE. In addi-
tion, it has recently been shown that radial glial cells in
the human cortex can directly produce either Tbr2-pos-
itive or ASCL-positive cells thereby generating both ex-
citatory and inhibitory lineages, respectively
[40] . Inter-
estingly, in this latter study the authors could not distin-
guish the distinct precursors for inhibitory neurons as all
ASCL-positive cells co-expressed Sox2 (a neural stem
cell/progenitor cell marker) and/or Tbr2. In rodents,
Mash1 has also been associated with the generation of
oligodendrocytes
[41] and the relevance of this in human
development is not yet known.
A study in the monkey cortex has revealed a temporal
perspective on interneuron generation and migration.
Not only was it confirmed that GABAergic cells were gen-
erated in the VZ/SVZ of the dorsal telencephalon (Mash1-
positive) and GE (Mash1-negative), these results suggest-
ed also that the site of origin dictated the birthdate of
interneurons, as well as their laminar positioning
[42] . To
summarize, the GE-derived interneurons arise during
early gestation and are located in the marginal zone (MZ)
and subplate (SP), whereas at later stages of gestation cor-
tically derived interneurons are generated. The lack of
time lapse analysis precludes any definitive confirmation
of the migratory routes adopted from the two sites of or-
igin; nonetheless, these data illustrate an evolutionary
conservation of Mash1-positive progenitors in the dorsal
telencephalon. Subsequent studies, driven largely by
Zecevic and colleagues, have broadened our understand-
ing of interneuron biology during human cortical devel-
opment
[43–46] . By analysing the expression profiles of
GE-associated transcription factors (Nkx2.1, Dlx1, Dlx2,
Lhx6 and Mash1) combined with an interneuron subtype
marker (calcium-binding protein, calretinin) and a pro-
liferation marker (Ki67), the authors have corroborated
the presence of a progenitor population within the VZ/
SVZ.
Ultimately, it would be ideal to identify the subtype
fate of interneurons generated in the dorsal telencepha-
lon; however, limitations of studying human tissue pre-
vent this. Abnormalities in cortical interneuron develop-
ment have been linked to a number of human disorders
(outlined in the section ‘Neurodevelopmental disorders
and interneuron development’) and a recent study inves-
tigating fetal or infant cases of holoprosencephaly with
severe ventral forebrain hypoplasia
[47] may shed light on
interneuron progenitor fates. In these cortices, a substan-
tial reduction was observed in interneurons positive for
the markers nitric oxide synthase 1, neuropeptide Y and
somatostatin (SST); in contrast, calretinin-positive cells
were still present. Interestingly, the interneuron subtypes
that showed the greatest reduction are derived from the
ventrally located GE, and the presence of the calretinin-
positive interneurons is indicative of an additional pro-
genitor population outside the ventral telencephalon. The
significance of these subtypes, and connection to the site
of origin, will become apparent in the following section,
where we discuss in detail the generation of interneuron
diversity.
I n t e r n e u r o n D i v e r s i t y
The first section of this review outlined the regions
within the telencephalon that generate interneurons, but
the next phase of interneuron development is fate deter-
mination and cortical positioning. Interneurons are a
heterogeneous population and the task of classifying
t he m i nt o s ubpo pu la ti on s i s a da un tin g o ne . O ve r t he pa st
few years various attempts have been made and more re-
cently a consortium of scientists specializing in anatomy,
physiology and development convened to create a unify-
ing nomenclature of GABAergic interneurons in the cor-
tex, the Petilla terminology (Petilla Interneuron Nomen-
clature Group)
[48] . We will briefly describe the main
approaches used for interneuron classification below;
however, a detailed description of interneuron subtypes
is beyond the scope of this review and has recently been
provided elsewhere
[8, 9, 48–50] .
Subtype classifications are generally based on 3 major
criteria: (1) the molecular profile, (2) morphology and
(3) electrophysiology of the interneuron. The first of these
rely on the expression of molecular markers and is prob-
ably the simplest and most commonly used. These in-
clude: the calcium-binding proteins parvalbumin (PV),
calbindin (CB) and calretinin (CR); certain neuropep-
tides, such as SST, vaso-active intestinal peptide (VIP),
neuropeptide Y, cholecystokinin and corticotropin-re-
leasing factor
[51–53] ; potassium channels such as Kv3.1
and Kv3.2
[54, 55] ; the secreted glycoprotein reelin [27] ;
nitric oxide synthase
[53] , and the serotonin receptor
Faux /Rakic /Andrew s /Britto
Neurosignals 2012;20:164–185
168
5-hydroxytryptamine 3A (5HT3aR) [56, 57] . Based on
their expression patterns, recent studies have shown that
PV, SST and 5HT3aR are exclusively expressed by 3 dis-
tinct subpopulations and when combined account for the
majority of GABAergic cells
[50, 56, 58] . Further subdivi-
sions of interneurons arise from the combinatorial ex-
pression of the molecular markers listed above
[27, 53, 58] .
The second major criterion, cell morphology, accounts for
differences in soma size and shape, dendritic and axonal
arborizations and location of postsynaptic connections.
Finally, electrophysiology depicts the firing properties
that characterize interneuron activity within the cortical
circuitry
[7, 8] . It is now widely believed that each of the
ab ove cr ite ri a sh ould be used when ide ntif yi ng or d escr ib-
ing specific interneuron subtypes. Interestingly, it was
noted at the end of the Petilla meeting that these segrega-
tions are primarily for the benefit of investigators trying
to categorize a diverse system governed by its role in neu-
romodulation. Regardless, these classifications have rec-
ognized the large diversity of interneurons that exists
across various regions of the cortex
[8, 27, 51, 58–63] .
The Generation of Interneuron Diversity
To comprehend how such a high level of diversity is
created, we need to adopt a developmental perspective
and follow the life span of an interneuron from birth to
maturation. If we do this, there are 3 key phases when the
identity of an interneuron can be influenced: (1) specifi-
cation at birth, (2) exposure to signals during migration
and final positioning in the cortical plate (CP) and
(3) synaptic maturation and connectivity that ultimately
defines the neuromodulatory function of an interneuron.
It becomes evident that these are either an intrinsic prop-
erty of the interneuron or the influence of extrinsic fac-
tors from the cortical surrounds. Nonetheless, there is
evidence to suggest that all 3 play a role in determining
the fate of an interneuron. We will focus here on the ro-
dent model, as the wealth of data allows us to present a
rationale for each phase of development.
The first event would state that interneurons are spec-
ified at the time of birth and therefore subtype specifi-
cation is largely defined within the GE. The obvious
molecular candidates would be transcription factors
( table 1 ), and Rubenstein and colleagues have been
influential in discovering an array of factors that define
the GE as a distinct developmental domain
[39, 64– 69] .
Dlx1 and Dlx2 are expressed throughout the SVZ of the
GE and confer an interneuron fate upon the newly born
cells. Distinct subtypes of interneurons are spatially and/
or temporally segregated within the pool of Dlx-positive
progenitors, and transplantation studies
[23, 70] , genetic
fate mapping
[28, 56, 71] and cell culture analysis [72]
have provided a broad map of subtype origin. More spe-
cifically, MGE-derived interneurons are mainly PV-pos-
itive fast-spiking basket cells and SST-positive intrinsic
bursting Martinotti cells, while all CGE-derived cells are
positive for 5HT3aR, exhibit a range of firing potentials
and morphologies, and are further subdivided by their
expression of VIP, CR and neuropeptide Y
[7, 8] .
A spatial bias also exists within the MGE itself as PV-
positive cells arise primarily from the ventral MGE and
SST-positive cells from the dorsal MGE
[73, 74] . Interest-
ingly, it appears that a gradient of sonic hedgehog activ-
ity is driving this spatial bias
[69, 75–77] . If these findings
suggest parity with the generation of interneuron diver-
sity in the spinal cord
[78] , then domain-creating tran-
scription factors would need to be present in the MGE.
Indeed, central to interneuron specification is an array of
transcription factors (Nkx2.1, Nkx 6.2, Lhx6, CoupTFI,
Cux 1, 2, Sox6 and Dlx5/6)
[29, 65, 79–87] ; however, ex-
pression patterns do not create clearly defined bound-
aries that are subtype specific. More recently, attempts
were made to delineate progenitor domains by the com-
binatorial expression of transcription factors
[39, 68] ;
once again, the borders are not sharply defined, and mul-
tiple subtypes could be produced within the progenitor
regions.
We have described specification occurring in a spatial
manner; however, increasing evidence suggests that a
temporal regulation also exists
[27, 60, 86] . Interneuron
genesis in mice takes place between E9 and E16, and the
peak production from the MGE occurs around E12–E13.
In contrast, the initiation and peak production of inter-
neurons from the CGE is around E12 and E15–E16, re-
spectively
[27, 60] . This temporal pattern is reflected by
the subtypes that are generated, for example, most SST-
positive Martinotti cells are predominantly born at E9,
SST- and CR-double-positive cells at E12 and most VIP-
positive cells at E15
[60, 86] . In comparison, although PV-
positive cells are produced throughout the entire genesis
period, PV-positive chandelier cells are produced at E15
[74] implying specific temporal delineation in subtype
generation. This developmental scenario is analogous to
the generation of pyramidal neurons, where the temporal
expression of transcription factors (Brn1/2, Svet1, Cux1,
Cux2) controls the sequential production of deep versus
superficial cortical neurons
[88] . Furthermore, as de-
scribed above, the temporal profile of interneuron sub-
type generation may exist in humans, albeit from differ-
ent cortical sources.
Migration and Lamination of Cortical
Interneurons
Neurosignals 2012;20:164–185
169
Overall, there is clear evidence to suggest that both the
progenitor location and time of birth are two highly in-
fluential factors in determining the fate of an interneu-
ron. Interestingly, many characteristics used to define an
interneuron are not evident until late postnatal ages and
even adulthood. Synaptic maturation of interneurons is a
protracted process strongly regulated by experience-
driven neural activity (this can span up to the first two
decades in humans). This leaves abundant time for inter-
neuron identity to be modified during migrat ion into the
CP and integration into functional circuits, leading us to
the second and third phases of interneuron specification
where extrinsic factors can influence interneuron iden-
tity ( table1 ). It has been shown that certain dorsalizing
signals, such as BMP4, can increase the number of PV-
positive cells, with a concomitant decrease in SST-posi-
tive cell number
[89] . Brain-derived neurotrophic factor
(BDNF) signalling also differentially alters interneuron
subpopulations both in vitro and in vivo
[31, 90, 91] . In
addition, cell morphology is modified by environmental
signals, such as BDNF, the soluble form of neural cell ad-
hesion molecule and even GABA, which all regulate axo-
nal and dendritic branching as well as synaptogenesis
[92–95] . Altered neuronal excitability may also play a role
in interneuron specification, as demonstrated recently in
an elegant study by De Marco Garcia et al.
[96] . This
Tab le 1. Genes involved in interneuron development
Role in interneuron
development
Transcription factors Ligand-receptor signalling
Proliferation -Catenin (Wnt-mediated) [230] Cyclin D2 [231]
Differentiation Cux1/Cux2 [82] GDNF/GFR␣1 [126]
Dlx1, 2, 5, 6 [39, 64, 65, 80, 85] Ryk [232]
Lhx6, 8 [69, 162] Shh [69, 75, 77]
Mash1 [37–39]
Subtype specification
MGE derived Lhx6 [69, 162] BMP/BMPR1 [89]
Nkx2.1 [72, 79, 162] BDNF/TrkB [31, 90, 91]
Nkx6.2 [86] Kir2.1 [96]
Sox6 [84]
CGE derived Coup-TFI [81]
Migration
Tangential Arx [157, 158, 218] BDNF/TrkB [31, 125]
Coup-TFII [29] CXCL12/CXCR4, 7 [144, 145, 183–186, 188]
Dcx [106, 107, 218] GDNF/GFR␣1 [126]
Dlx1, Dlx2 [19, 160, 161] HGF/SF [115]
Lhx6 [87, 156, 159] Netrin 1 [189]
NRG1/ErbB4 [99, 146, 149]
p35 [108]
Guidance through Eph/ephrin [141, 142]
ventral telencephalon Robo [136, 137, 140]
Sema [129, 130, 140]
Regional distribution GDNF/GFR␣1 [128]
Switch to radial Sox6 [83, 84] Connexin 43 [182]
Netrin 1 [189]
Lamination and Sox6 [83] BDNF/TrkB [125]
termination Fezf2 [204] CXCL12/CXCR4/CXCR7 [144, 184, 186, 187]
KCC2 [207]
Kir2.1 [96]
p35 [108]
Reelin [180, 200, 202, 203]
Faux /Rakic /Andrew s /Britto
Neurosignals 2012;20:164–185
170
study found that altering the electrical activity of CGE-
derived interneurons, by overexpressing the potassium
channel Kir2.1, caused a pronounced change in the mor-
phology of CR- and reelin-positive cells. In contrast, VIP-
positive neurons were unaffected. Interestingly, the al-
teration in cell morphology only arose when neuronal
activity was modified after postnatal day 5, a time well
beyond genesis in the GE.
The extrinsic activation of intracellular signalling
pathways is crucial in modulating neuronal excitability,
and it is hardly surprising that molecular changes arise
during synaptogenesis. For this reason many believed
that interneurons were ‘naïve’ until these later stages of
development and this may not be far from the truth. Tak-
en together, the studies described above indicate that in-
terneurons within the CP are not necessarily naïve, but
are restricted in fate by transcription factor expression at
birth and are further refined following exposure to the
cortical environment and integration into microcortical
networks. It is therefore becoming increasingly apparent
that the combination of all 3 phases in interneuron devel-
opment contributes to generating interneuron heteroge-
neity in the adult cortex.
Tangential and Radial Migratory Routes
Neuronal migration constitutes a fundamental pro-
cess during cortical development, and through a se-
quence of highly orchestrated events the characteristic
laminated structure of the adult cortex is formed. The
ability of neurons to navigate the cellular milieu while
integrating multiple guidance cues is a marvel in itself,
and great efforts are made to comprehend the molecular
basis of this process. The cellular events during cortico-
genesis provide an elegant model for investigating such
processes as the two neuronal populations have adopted
distinct migratory behaviours to eventually reside in a
common terminus. Pyramidal neurons generated locally
in the neuro-epithelium migrate radially from progeni-
tors in the VZ/SVZ towards the CP, whilst interneurons
generated in a subcortical progenitor zone embark on
tangential migration (parallel to the ventricular surface)
before entering the CP. Regardless of subtype or site of
origin, all interneurons must migrate vast distances to
reach a final destination.
There are 3 major routes of migration observed for
interneurons during corticogenesis; the first is along
well-defined tangential paths from the GE towards the
corticostriatal junction and into the cortical wall, the
second encompasses multidirectional migration within
these migratory paths and the third involves a shift to-
wards a radial trajectory so as to enter the CP ( fig.1 ).
These last 2 routes will be referred to as ‘intracortical’
migration, indicating the phase of interneuron move-
ment into the laminated CP generated by pyramidal
neurons. Although we focus this review on cortical in-
terneurons, these migratory streams are also utilized by
hippocampal interneurons, which traverse the cortex
before entering the hippocampal primordium in a stage-
dependent manner
[17, 19, 23, 97] . Various guidance
molecules, substrates and intrinsic programming sig-
nals are required to direct the migrating interneurons to
their correct laminar position, and these will be dis-
cussed in the following sections. First, however, we will
describe the dynamic cellular mechanisms of interneu-
ron movement, as this is instrumental for guidance-di-
rected migration.
The Branching Dynamics of Migrating Interneurons
Unlike pyramidal cells, which are associated with ra-
dial glial fibres and migrate primarily in a straight trajec-
tory, migrating interneurons navigate without any obvi-
ous physical support and change direction frequently. To
do so, and similar to growing axons, interneurons use
their leading process (neurite) as a compass, having a
growth-cone-like structure at the distal end. Whilst ax-
ons manoeuvre the growth cone towards or away from
chemotactic cues, interneurons continuously produce
multiple branches from the leading neurite, subsequently
selecting a single branch oriented in the direction of the
attractive cue
[98, 99] ( fig.2 ). This migratory behaviour
is disparate to the chain migration of olfactory interneu-
rons in the rostral migratory stream
[10 0] , but turns out
to be required for directional guidance. The individual
searching behaviour of cortical interneurons is evidenced
by vigorous and dynamic neurite branching, and inter-
mittent leaps made by the nucleus to advance the cell (nu-
cleokinesis). This saltatory nuclear translocation appears
uncorrelated to the dynamic branching of neurites at the
leading edge of the cell
[98, 101] . A recent study examin-
ing the relationship between nucleus movement and the
temporal extension and retraction of neurites has high-
lighted independence between these two cellular mecha-
nisms, that is, once the choice of a leading neurite is made,
the nucleus moves despite the degree of branching in the
neuritic arbour
[10 2] . This is not to say that neuritic
branching is decoupled from nucleokinesis, as signalling
unequivocally occurs from the growth cone to the cell,
but rather these cellular dynamics represent a very effi-
Migration and Lamination of Cortical
Interneurons
Neurosignals 2012;20:164–185
171
cient manner for searching and moving through an un-
known environment.
The process of nucleokinesis occurs in two phases.
First, cytoplasmic organelles (i.e. the Golgi/centrosome)
move forward and separate from the nucleus. This is fol-
lowed by the splitting of the centrosome and nuclear
translocation towards the organelles. Interestingly, close
observat ion of t his nuclear mov ement r eveal ed t hat when
an interneuron is migrating in a relatively constant direc-
tion, the nucleus tends to alternate between left and right
leading neurite branches
[99] . Nuclear movement occurs
through actomyosin-dependent pushing forces from the
rear of the cell and microtubule-associated pulling forces
ahead of the nucleus
[98, 103, 104] . One of the key steps
in interneuron migration is the stabilization of the micro-
tubules in the leading neurite. Disruption in microtubule
dynamics, for example through the deletion of microtu-
bule-associated proteins, such as lissencephaly 1 (Lis1)
[10 5] and doublecortin (Dcx) [106, 107] , or upstream reg-
ulators like p35/Cdk5
[10 8 , 10 9] , leads to abnormal neu-
rite branching and causes the misguided migration of the
cells.
Tangential Interneuron Migration
Tracing, fate-mapping and loss of function analyses
have shown 3 major migratory paths that interneurons
follow from their origins in the ventral telencephalon to
the cortex
[110–112] . Specifically, an early cohort (E12 in
the mouse) first reaches the cortex and migrates at the
level of the preplate. A second and more prominent co-
hort migrates predominantly through the IZ. At the later
stages of corticogenesis (E14–E15) and after the forma-
tion of the CP, 3 distinct tangential migratory streams are
evident in the developing cortex, located in the MZ, SP
and lower IZ/SVZ ( fig.1 )
[17, 30 , 112] . Thus, intricate mo-
lecular mechanisms including an array of motogenic fac-
tors, chemotactic guidance cues, transcription factors
and neurotransmitters are employed by interneurons
throughout tangential migration ( table1 )
[113, 114] and
we will discuss each in turn.
Motogenic Cues
A number of soluble factors have been proposed to
play a role in cortical interneuron migration by acting as
‘promovement’ or motogenic factors . For instance, hepa-
tocyte growth factor/scatter factor enhances the migra-
tion of cells away from the ventral telencephalon, and loss
in its activity causes undirected migration of interneu-
rons within the GE leading to a reduction in the number
of interneurons in the cortex
[115] . Members of the neu-
rotrophin family have also been proposed as motogenic
factors in the migration of interneurons. Neurotrophins
are widely expressed in the developing cortex
[116–119]
and interneurons express the tyrosine kinase receptors
TrkB and TrkC, the cognate receptors for neurotrophins
[120, 121] . Both BDNF and neurotrophin 4 stimulate in-
terneuron migration, and analysis of the TrkB-null cor-
tex revealed a significant reduction in the number of CB-
positive interneurons
[31] . Recently, the calcium-depen-
dent activator protein for secretion 2 has been shown to
promote BDNF secretion, and analysis of null mice for
this protein revealed a decreased number of GABAergic
neurons and their synapses in the hippocampus
[122] ,
thus confirming a role for BDNF in interneuron migra-
tion. However, the role of BDNF in cortical interneuron
development is not without debate. Other studies have
suggested that disruption of BDNF signalling leads to
downregulation of CB and other neuropeptides expressed
in interneurons
[91, 123, 124] . This would cast some
doubt as to whether the reduction of interneuron num-
bers in the absence of TrkB reflects an actual defect in
migration or simply a reduction of cell markers. Addi-
tionally, changes to the endogenous levels of BDNF may
impair cortical development, and the effects on interneu-
ron positioning may be a secondary phenotype. This is
indeed the case when analysing the nestin-BDNF trans-
genic mice, where exogenous levels of BDNF not only led
to an inappropriate segregation of Cajal-Retzius cells and
interneurons in the MZ, but altered cortical organization
and impaired final radial migration of interneurons
[125] .
The neurotrophin glial cell line-derived neurotroph-
ic factor is highly expressed in interneuron migratory
pathways in the cortex
[126] . Members of the glial de-
rived neurotrophic factor ligand family signal by bind-
ing to glycosylphosphatidylinositol-anchored receptors,
GFR ␣ 1–4 , in collaboration with the RET receptor tyrosine
kinase
[127] . Interneurons in GFR ␣ 1 -null mutants were
found misrouted in the MGE and significantly reduced
in the cortex. A follow-up study, using the homozygous
GFR ␣ 1 -null rescued by expression of Gfra1 gene from the
Ret locus, revealed regionalized loss of PV-positive inter-
neurons
[128] . This presents a scenario where guidance
molecules may guide certain subtypes of interneurons to
discrete regions of the cortex.
Chemotactic Molecules
Once generated in the MGE, postmitotic interneurons
journey towards the cortex by first traversing the devel-
oping LGE (striatum primordium) en route to the corti
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Neurosignals 2012;20:164–185
172
costriatal junction. Guidance cues play a key role in di-
recting interneuron migration in this area. Most will be
familiar with chemo-attractive and chemorepulsive cues
required for axon guidance; interestingly, these same
families of proteins are involved in the guidance-directed
migration of interneurons. To avoid entering the stria-
tum, migrating interneurons express neuropilins (Nrp1
and Nrp2) and plexin coreceptors that respond to the che-
morepulsive ligands semaphorin (Sema) 3A and 3F ema-
nat in g f ro m t he st ri at al m an tl e
[129] . In addition, the pro-
teoglycan chondroitin-4-sulphate is expressed in the stri-
atal mantle
[13 0] , which, in conjunction with the
semaphorins, creates an exclusion zone for migrating in-
terneurons to channel into adjacent paths and thus define
the formation of migratory routes into the cortex. The
Sema proteins are also active in the neocortex and act to
direct interneuron migration in the tangential streams,
preventing them from entering the CP
[131] .
The chemorepulsive ligand Slit1 is strongly expressed
throughout the VZ and SVZ of the GE as well as the pre-
optic area
[13 2–135] and the corresponding receptor
roundabout (Robo) is expressed by interneurons. The
complementary expression patterns of Slit-Robo suggest
Slit proteins might repel interneurons from the GE to the
cerebral cortex
[13 6 –139] . Surprisingly, no defects in the
tangential migration or differences in the number or dis-
tribution of interneurons (GABA-, Lhx6- or Dlx2-posi-
tive) were detected in the cortices of Slit1/Slit2 double
mutant
[111] . Nonetheless, the analysis of two different
Robo1-deficient transgenic models have shown a signifi-
cant influx of CB-positive cells within the developing
striatum, as well as an increased number of interneurons
within the developing and adult cortex
[13 6 , 137] . This
suggests that Robo1-null effects could be Slit indepen-
dent, and this has been confirmed with the recent discov-
ery that Robo1 modulates semaphorin-neuropilin/plexin
signalling to steer interneurons around the striatum and
into the cortex
[14 0] .
Keeping with the classic collection of guidance cues,
the membrane-bound ephrin and Eph receptor tyrosine
kinases (Eph) also play a role in interneuron migration.
Experimental in vitro and in vivo evidence has revealed
the involvement of ephrins in directing migration and
enhancing the motility of neurons
[141, 14 2] . Ephrin A5
and its receptor EphA4 are complementarily expressed in
the VZ and SVZ of the GE, respectively, and CB-positive
cells isolated from the MGE express the EphA4 receptor
[141] . In vitro stripe assays have demonstrated that both
ephrin A5 and ephrin A3 are potent chemorepellents for
MGE-derived neurons. Downregulation of the EphA4 re-
ceptor, using siRNA, reduced the repulsive effect of eph-
rin A3 implicating EphA4 in mediating in part the repul-
sive effects of ephrin A3
[14 2] . Together, these results sug-
gest that Eph/ephrin signalling acts as a repulsive cue that
restricts cort ical interneuron migration from inappropri-
ate regions and are contributing factors in defining the
migratory route of cortical interneurons.
Even though inhibitory cues are necessary to guide
migration, interneurons are also directed towards the
cortex in response to attractive cues. One such candidate
is the chemokine CXCL12 (stromal cell-derived factor,
SDF1) which signals through the receptors CXCR4 and
CXCR7. During early corticogenesis (up to E14.5),
CXCL12 expression is high in the MZ and SVZ, whereas
at later stages, expression remains high in the MZ but is
dramatically reduced in the SVZ
[143] . The receptors
CXCR4 and CXCR7 are expressed on tangentially mi-
grating interneurons
[14 4] . It has been shown that
CXCL12 attracts interneurons from the MGE, guiding
them to the tangential migratory streams and maintain-
ing them here until the appropriate radial migratory cue
is received (see radial migration below)
[145] .
A second candidate, the neuregulin 1 (NRG1) family
of proteins, is essential for interneurons to leave the MGE,
travel through the LGE permissive corridor, circumvent
the corticostriatal notch and enter into the cortical wall
[14 6] . There are several lines of evidence to suggest a role
for NRG1 signalling during interneuron migration.
Flames et al.
[14 6] found that different isoforms of NRG1
play distinct roles along the migratory path. The mem-
brane-bound isoform of NRG1 (type III) is found highly
expressed by so-called corridor cells present in the SVZ
but not the VZ of the LGE. Together with the inhibitory
action of semaphorins emanating from the striatum, a
permissive corridor is created along the SVZ for inter-
neurons to traverse the LGE. To cross the corticostriatal
notch, interneurons require the secreted isoforms of
NRG1 (types I and II), which are expressed in the neocor-
tex and act as a long-range chemo-attractant for migrat-
ing interneurons. The immediate action of interneurons
exposed to an exogenous source of secreted NRG1 is to
alter the direction of migration by the extension of a new
leading neurite in the direction of the source ( fig.2 )
[99] .
In the long term, when cortical NRG1 expression is re-
duced, there is a concomitant accumulation of ErbB4-
positive interneurons at the corticostriatal junction
[147]
and the complete loss of NRG1 in the forebrain leaves in-
terneurons incapable of leaving the MGE
[14 6] .
The expression of ErbB4 (NRG1 receptor) in cortical
interneurons
[14 8, 149] is conserved across a number of
Migration and Lamination of Cortical
Interneurons
Neurosignals 2012;20:164–185
173
species including rodents, macaques and humans [150] ,
and NRG1 has reproducibly emerged as being a candidate
susceptibility gene for schizophrenia
[151–155] . A dys-
functional GABAergic system is an underlying element
in schizophrenia, and the link between NRG1 and early
interneuron migration suggests a developmental aetiol-
ogy. The importance of this will be discussed when we
review neurodevelopmental disorders associated with in-
terneuron migration.
Transcription Factors
The idea that transcription factors are involved in mi-
gration is quite removed from the classic role of enhanc-
ing or repressing genes for cell fate determination; how-
ever, this can be achieved through the regulation of guid-
ance cue receptors. For example, loss of function studies
for Lhx6 lim-homeobox transcription factor
[87, 156] and
Arx homeodomain transcription factor
[15 7, 15 8] in
mouse brain slices have shown impeded tangential mi-
gration of interneurons into the cortex. Recently Lhx6
has been shown to mediate its effects through promoting
expression of receptors involved in interneuron migra-
tion (ErbB4, CXCR4 and CXCR7), and through promot-
ing the expression of transcription factors either known
(Arx) or implicated (bMaf, Cux2 and NPAS1) in control-
ling interneuron development
[15 9] .
The homeobox genes Dlx1/2 are essential not only for
the migration of interneuron precursors but also for their
maturation in the cortex
[19, 160] . Recent evidence sug-
gests that Dlx1 and Dlx2 regulation of interneuron mi-
gration depends on its ability to restrain neurite out-
growth. These effects appear to be mediated by Dlx1/2
repression of several genes involved in regulating cyto-
skeletal dynamics including PAK3 and MAP2
[16 0] .
PAK3 expression is low in migrating interneurons and
upregulated upon arrival at the cortex when it is required
for neurite outgrowth. The repressive action of Dlx1/2 on
PAK3 in MGE-derived interneurons is critical in pro-
moting tangential migration, and this was elegantly dem-
onstrated by reducing the aberrant PAK3 and MAP2 ex-
pres sion i n the Dl x1/2 doub le mutant to subst ant ia lly res -
cue the tangential migration defects
[16 0] . In a parallel
study, Le et al.
[161] found that Dlx1/2 mediated the re-
pression of the receptor Nrp2 and therefore may facilitate
migration through regulating the response to class 3
semaphorins.
The homeodomain factor Nkx2.1 is specifically ex-
pressed in MGE interneuron progenitors and required for
the specification of cortical interneuron subtypes
[79,
162] . The expression of Nkx2.1, however, is downregu-
lated in interneurons entering the migratory route in the
cortex [16 3] , and this downregulation is in fact an active
step taken by cortical interneurons to coordinate their
programmes of differentiation and migration
[163] .
Nkx2.1 was also shown to repress Nrp levels. The ectopic
expression of Nkx2.1 in migrating MGE-derived cells
rendered them insensitive to Sema3A/Sema3F chemore-
pulsion, likely due to a reduction in the expression of
Nrp1 and Nrp2 [163] . Collectively, the above examples ex-
emplify the dynamic temporal expression of transcrip-
tion factors and how this function is required not only for
interneuron differentiation, but also for the coordination
of interneuron migration.
N e u r o t r a n s m i t t e r s
Neurotransmitters are recognized more for a central
role in synaptic transmission and the functionality of
cortical networks; however, increasing evidence suggests
a role in regulating interneuron migration. An assort-
ment of electrophysiological and pharmacological stud-
ies have shown that neurotransmitters play a combinato-
rial role in guiding interneurons across the corticostriatal
junction and maintaining the migratory distribution
within the cortical wall. To outline the expression profile
of neurotransmitters and their corresponding receptors
during migration, GABA is present along the main mi-
gratory routes and interneurons express GABA
A and
GABA
B receptors [164–16 6] . Dopamine is expressed in
the MGE and its corresponding D
1 and D
2 receptors are
expressed on interneurons
[167, 168] and functional glu-
tamate receptors are present on interneurons migrating
in the IZ
[169–17 1] . This story becomes interesting when
we examine the phenotypes of the individual receptor
knockouts or use of pharmacological blockers through-
out the migratory phase.
During corticogenesis, GABA A receptors bind GABA
with higher affinity than mature neurons
[172] and the
ambient levels of GABA along the migratory route elicit
a depolarizing response to modulate migration
[16 4] .
Blocking this activity by the treatment of bicucilline or
neutralizing GABA antibodies leads to an accumulation
of interneurons at the corticostriatal junction; conversely,
the addition of GABA enhanced migration into the corti-
cal wall
[16 4] . Several studies have demonstrated the vari-
ation in GABA
A receptor subunit expression during de-
velopment
[76, 173] and a recent profiling of single-cells
combined with electrophysiological recordings has noted
that interneurons migrating in the cortex have a higher
affinity, and increased responsiveness to GABA, com-
pared to interneurons in the MGE
[16 6] . This regional
Faux /Rakic /Andrew s /Britto
Neurosignals 2012;20:164–185
174
a
b
Fig. 3. Factors affecting interneuron lami-
nation in the rodent cortex.
a During em-
bryonic development, interneurons are
maintained in the tangential migratory
streams in the MZ, SP and SVZ by various
cues, only transiently entering the CP. Dis-
ruption in CXCR4 signalling results in the
premature invasion of interneurons into
the CP, subsequently disrupting lamina-
tion.
b By the completion of interneuron
lamination in the adult, MGE-derived PV-
and SST-positive interneurons predomi-
nantly occupy deeper cortical layers (lay-
ers IV–VI), while CGE-derived 5HT3aR-
positive cells primarily occupy more
superficial layers (layers II/III). Disrup-
tion to reelin signa lling ( reeler mutant) re-
verses the lamination of these cells. Simi-
larly, a disruption in p35 signalling revers-
es interneuron lamination with a partial
loss in PV- and SST-positive cells. Altera-
tions in GFR ␣ 1 signalling also cause the
regiona lized loss of a subpopu lation of PV-
positive cells. In comparison, ablation of
Fezf2 expression causes a shift in PV- and
SST-positive interneurons to more super-
ficial layers.
Fig. 2. Interneuron morphology and
branching dynamics during migration.
Interneurons respond to guidance cues by
changing the direction and length of a
leading process. Each neuritic process has
a growth-cone-like structure at the distal
end that is used to scan the environment
and determine the direction of movement.
Neurites will extend towards chemo-at-
tractants (+), i.e. CXCL12 and neuregulin,
and are repelled by chemorepellents (–),
i.e. semaphorin and ephrin. Once a lead-
ing process is determined, the soma moves
to the branch point of the leading neurite,
and other cell processes retract. New
branches are formed and through a cycle
of neurite extension and retraction the in-
terneuron can change the direction of mi-
gration.
Migration and Lamination of Cortical
Interneurons
Neurosignals 2012;20:164–185
175
selective response to GABA was accompanied with al-
terations in GABA isoforms present on individual neu-
rons and highlights the maturation of interneurons dur-
ing the migration process. In addition, selective antago-
nists to the GABA
B receptors result in an accumulation
of interneurons in the VZ/SVZ and a reduction in the
migration through the CP and MZ
[165] . It is unclear
whether this change in distribution arises initially from
misguided routes in the MGE or variation in radial mi-
gration within the cortex, time lapse analysis would be
beneficial in elucidating this query.
The expression of the dopamine receptors D
1 and D
2
on interneurons and the MGE being a source of dopa-
mine suggests a role for this neurotransmitter in migra-
tion
[16 8] , and indeed this is the case. Intriguingly, the
individual activation of D
1 or D
2 receptors produce op-
posing effects
[167] . Pharmacological blocking of D
1 re-
ceptor activity, which induces concomitant activation of
the D
2 receptor, decreases the migration of interneurons
into the cortex and implies that D
1 receptor activation
promotes migration whereas D
2 receptor activation is in-
hibitory. This was confirmed further by analysis of the
individual receptor knockouts. Although there was no
change in the total number of interneurons in the CP/
MZ, the D
1 receptor knockout showed a significant de-
crease in the number of interneurons in the IZ/SVZ,
whilst the D
2 receptor knockout exhibited an increase in
interneurons in this domain
[167] . A recent study inves-
tigati ng the downstream molecular mechanisms of D
2 re-
ceptor activation in zebrafish
[174] has illustrated the
conserved nature of this signalling pathway for interneu-
ron development and the importance of maintaining
neurotransmitter homeostasis to promote the correct mi-
gration and positioning of cortical interneurons.
As described above, a vast array of motogenic and che-
motactic cues, transcription factors and neurotransmit-
ters instruct and guide the tangential migration of the
interneurons from the ventral telencephalon into the
neocortex. Some of these factors also influence the intra-
cortical migration and lamination of the interneurons.
We will discuss these processes and the molecules in-
volved below.
Intracortical Migration of Interneurons
Once interneurons arrive in the cortex, different
modes of migration are employed. We refer to this as in-
tracortical migration. These migratory behaviours in-
clude: (1) the multidirectional migration within tangen-
tial routes
[175–17 8] , (2) the radial migration for cells
moving away from the tangential routes into the CP
[99]
and (3) the ventricle-directed migration from the IZ/SVZ
towards the VZ
[179] . The second migratory mode en-
compasses both inward radial migration towards the CP
from the MZ
[31, 175, 176] and outward radial migration
towards the CP from the IZ/SVZ
[31, 176, 177, 180] .
Using flat-mount cortical preparations and real-time
microscopy, several groups observed that a substantial
proportion of embryonic GABAergic neurons exhibit the
multidirectional migration, where the cells move in all
directions within the MZ
[175, 176] and VZ [17 7] . Fur-
thermore, Tanaka et al.
[178] suggest that GABAergic
cells, once reaching the MZ, are liberated from regulation
by guidance signals and appear to change direction un-
predictably, in a process they term ‘random walk’. The
random walk behaviour potentially contributes to the
spread of interneurons throughout the cortex; however,
we know that the cortex is not uniform and cortical re-
gions vary in interneuron number and subtype content
[49] . If this is the case, the distribution of interneurons is
not entirely random, but guided to a certain extent by ex-
trinsic or intrinsic signals. Interestingly, Cajal-Retzius
cells display multidirectional orientation comparable to
the leading neurite angle of interneurons located in close
proximity
[175] ; thus, Cajal-Retzius cells may provide po-
sitional cues for migrating interneurons. Furthermore, as
Cajal-Retzius cells play a role in early regionalization of
the cerebral cortical neuro-epithelium
[181] , it is tempt-
ing to speculate that they can also inf luence the pattern-
ing of the cortical interneurons.
The invasion of the CP by MGE-derived neurons from
both the IZ (moving outward) and from the MZ (moving
inward) has been shown using in vitro transplantation
studies
[31] or in vivo with the glutamic acid decarboxyl-
ase 67 (GAD67)-green fluorescent protein (GFP) knockin
line
[176–17 8] . GAD67 is an interneuron-specific enzyme
required for GABA synthesis, and the GAD67-GFP
knockin line has been instrumental for real-time imag-
ing of interneuron migration in cortical slices. Tanaka et
al.
[178] propose that MGE-derived interneurons migrate
first to the cortical SVZ, then from the SVZ to the CP, ac-
cumulating transiently in the MZ. The existence of this
outward migration was confirmed and identified as be-
ing characteristic of late-born interneurons (after E15.5)
[18 0] . Finally, there is evidence that cortical interneurons
may migrate inwardly towards the VZ, in what has been
termed ‘ventricle-directed migration’, perhaps to receive
signals that may ultimately assist them in correctly inte-
grating into the cortex
[179] .
It has been suggested that the switch from tangential
to radial migration is dependent on neurite branching
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Neurosignals 2012;20:164–185
176
dynamics. While migrating in the tangential migratory
streams, interneurons maintain the orientation of the
leading neurite parallel to the ventricular surface/pia. In-
terneurons may linger in the migratory streams for long
periods of time
[178] before receiving the signal to move
into the CP. Once received, the angle of the leadi ng branch
changes from small to nearly orthogonal, and the switch
from tangential to a radial migratory mode is achieved
[99] . From what we know about the guidance-directed
migratory behaviour exhibited by interneurons, any cue
governing a switch to radial migration needs to be highly
regulated both spatially and temporally during cortico-
genesis.
T he m olec ul ar cues gov er ni ng th is sw itch in tr ajec tory
are still largely unknown; however, some possible candi-
dates have been identified. The downregulation of con-
nexin 43 expression in interneurons significantly de-
creased the percentage of radially oriented cells, with a
concomitant increase in tangential cell orientation
[182] .
These studies also verified that the adhesive function of
connexin 43, and not formation of hemichannels, was re-
quired for interaction with the radial glia. Another regu-
lator, the HMG-box-containing transcription factor Sox6
plays a role as loss of Sox6 in MGE-derived cells causes an
accumulation of interneurons in the MZ. This has been
interpreted as a defect in the transition from tangential to
radial migration
[83, 84] .
Another approach to control radial migration could be
the downregulation of cues required for anchoring inter-
neurons in the MZ during the horizontal dispersion
phase. This is observed w ith the chemokine CXCL12 and
its receptors CXCR4 and CXCR7. As described above,
CXCL12 expression in the MZ and SVZ
[143] is thought
to attr ac t corti ca l inter neu rons
[145] . L os s of CXC L12 si g-
nalling increases interneuron branching
[183] and dra-
matically disrupts tangential migration [144, 145 , 18 4 –
188] , resulting in the premature entry of interneurons
into the CP and abnormal lamination ( fig. 3 a). Thus,
CXCL12/CXCR signalling may play a dual role, initially
attracting interneurons to the neocortex and subsequent-
ly maintaining their migration in the tangential streams
until the correct radial signal is received.
Other examples of signalling systems required to
maintain interneurons in the tangential streams include
the interaction between netrin 1 and ␣ 3  1 -integrin. An
increase in the number of cells switching from tangential
to radial migration is observed when this interaction is
perturbed
[189] . Finally, a possible role for Cajal-Retzius
cell and pyramidal neuron involvement is hinted at in the
nestin-BDNF transgenic mouse where inappropriate seg-
regation of Cajal-Retzius cells and altered cortical orga-
nization impair the final radial migration of interneu-
rons
[125] . Co ns id er ab le prog re ss ha s b een ma de in re ce nt
years regarding radial migration, and future studies will
help illuminate other factors involved in this essential
process.
I n t e r n e u r o n L a m i n a t i o n
The characteristic 6-layered structure of the mature
mammalian cortex is formed largely through the radial
migration of the pyramidal neurons. During early corti-
cal development, the first wave of postmitotic pyramidal
neurons moves rapidly from the VZ/SVZ to the pial sur-
face, forming a thin mantle layer of cortical primordium
called the preplate layer. A second wave of neurons splits
the preplate layer into the superficial layer I (MZ) and a
deeper SP layer, establishing the CP in between. The CP
is then expanded in an ‘inside-out’ manner, with layer VI
forming first, and subsequent waves of neurons migrat-
ing past their predecessors to form the more superficial
layers (layers V to II)
[19 0 –193] .
Althoug h cortical interneu rons approach the CP from
a subcortical source, it is believed that a similar inside-out
pattern of lamination occurs, with early-born cells occu-
pying deeper layers and late-born cells populating super-
ficial layers
[108, 175, 180, 193–196] . There are, however,
exceptions to this rule as it was observed that the early-
born cells actually occupy 2 peak locations, a large peak
around layer V and a minor peak around layer II/III
[19 7] .
Further studies in the rat found that while PV-positive
cells did follow the inside-out layering pattern, CR-posi-
tive cells followed an outside-in route, with early-born
cells located in layer II/III and late-born cells in layers V–
VI
[19 8] . It has since become apparent that the final des-
ti nation of interneu rons in t he CP is not solely depend ent
on the time of generation, but is also subject to the site of
origin. While cells derived from the MGE follow the loca-
tion of the pyramidal cells born at the same time
[60, 70,
195] , CGE-derived cells primarily populate the outer cor-
tical layers regardless of when they are generated
[27, 28,
57, 199, 200] ( fig.3 b).
Cues Controlling Interneuron Lamination
Cortical lamination in the mouse begins around E11
and is completed by approximately postnatal day 14. In-
terestingly, although a small number of interneurons
have been observed moving in and out of the CP at early
stages of corticogenesis
[31, 175 –177] , they do not become
Migration and Lamination of Cortical
Interneurons
Neurosignals 2012;20:164–185
177
established in their correct layer until late embryonic/ear-
ly postnatal stages, well after their contemporaneously
born pyramidal neuron counterparts
[18 0, 20 0] . It has
been suggested that cues from the cortex, rather than in-
trinsic genetic programming, controls interneuron lami-
nation
[19 5, 201] ( table 1 ). One well-known molecule
thought to play a major role in cortical lamination is the
secreted extracellular matrix protein reelin. Loss of reelin
signa lling reverses the la mination of the cortex to a n out-
side-in pattern, whereby late-born pyramidal neurons are
unable to migrate past the early-born cells
[18 0, 191] . Ab-
normal interneuron layering is also observed with dis-
rupt ed r eel in signall ing ( f ig.3 b)
[180, 200, 202, 203] ; how-
ever, there is some contention to whether this is the direct
action of reelin or a secondary effect of disorganized py-
ramidal neuron layering. Work by Hammond et al.
[203]
suggests that the laminar position of late-born interneu-
rons (not early-born) is dependent on reelin signalling,
whereas Pla et al.
[20 0] found that interneurons were de-
pendent on the location of pyramidal neurons and not
reelin signalling. Both studies utilized chimeric models
of transplanting wild-type cells into a Dab1 mutant (in-
tracellular adaptor molecule for reelin signalling), and
even though their interpretations differ, one underlying
phenomenon remains the same: the influence of pyrami-
dal neurons on directing interneurons into the appropri-
ate laminar position.
This line of re asoning has been explo red recently in an
elegant study by Lodato et al.
[204] . Analysis of the Fezf2
knockout revealed that the loss of subcerebral pyramidal
neurons and replacement by callosal pyramidal neurons
causes the abnormal distribution of specific interneuron
subtypes ( fig.3 b). Furthermore, they showed that differ-
ent types of glutamatergic pyramidal neurons effectively
recruit specific subtypes of interneurons into their im-
mediate vicinity. Thus, it appears that the identity of a
pyramidal neuron, as well as its location, can control the
laminar fate of an interneuron. The molecular mecha-
nisms used by pyramidal neurons in this attraction re-
main unknown.
A number of other signalling molecules have been
shown to affect interneuron positioning in the cortex.
Disruption in the glial derived neurotrophic factor recep-
tor, GFR ␣ 1 , causes the loss of a subset of PV-positive in-
terneurons in discrete regions of the cortex, predomi-
nantly in the visual and frontal cortices
[128] . Abnormal
interneuron lamination, and partial loss of PV- and SST-
positive interneurons, is also observed in p35 knockout
mice [Rakic, Faux and Parnavelas, pers. commun.,
108
( f ig.3 b). During corticogenesis, p35 is the primary activa-
tor of Cdk5, a serine-threonine kinase, which phosphor-
ylates proteins associated with the cytoskeleton and
thereby plays a pivotal role in neuronal migration [2 05,
206] . Disruptions to the tangential and radial migration
of the cells, for example by disrupting the CXCL12/
CXCR4 and BDNF/TrkB signalling pathways, can also
greatly affect their laminar position
[125, 145, 184, 187,
189] . Furthermore, neuronal activity has been shown to
affect interneuron layering postnatally. Overexpression
of the potassium channel Kir2.1 alters neuronal excitabil-
ity by lowering the resting membrane potential of the cell.
When induced between postnatal days 0–3 in CGE-de-
rived interneurons, an aberrant increase in CR- and ree-
lin-positive cells is observed in deeper cortical layers and
morphological alterations only after postnatal day 5
[96] .
Therefore, it is clear that lamination is influenced by
multiple mechanisms which we have only just begun to
identify.
The Stop Signal
In comparison to our current, albeit limited, knowl-
edge of the signals involved in lamination, even less is
known about the cues that direct an interneuron to stop
migration in the correct laminar position and to start ar-
borization. One study, by Bortone and Polleux
[207] , has
suggested that interneurons stop migrating in response
to GABA, but only after the interneuron has switched
from a depolarizing to a hyper polarizing state in response
to GABA activation. This switch in responsiveness fol-
lows the upregulation of the potassium/chloride exchang-
er KCC2
[208] . Low levels of KCC2 expression force the
cell into a depolarizing state following GABA stimulation
promoting cell migration. An increase in KCC2 expres-
sion reverses the electrochemical potential by extruding
chloride ions from the neuron. This results in GABA-
stimulated hyperpolarization and causes the cell to stop
migrating. The obser ved upregulation of KCC2 was non-
synchronous, thus making it difficult to determine pre-
cisely which interneuron subtypes terminate migration
first
[207] . It has recently been shown, however, that
MGE-derived interneurons upregulate their KCC2 ex-
pression before CGE- derive d cells, sug gesti ng that MGE-
derived subpopulations stop radial migration before
CGE-derived cells
[19 9] . Many questions remain regard-
ing the termination of interneuron migration, such as
what regulates KCC2 expression. Perhaps more intrigu-
ing, can various interneuron subtypes respond different-
ly to available intrinsic or extrinsic signals to promote
termination and differentiation in defined laminar posi-
tions? These and many more questions will drive the in-
Faux /Rakic /Andrew s /Britto
Neurosignals 2012;20:164–185
178
terneuron field into the future, as we are only beginning
to understand the intricacies of generating the functional
balance between pyramidal neurons and interneurons.
Neurodevelopmental Disorders and Interneuron
Development
In the adult brain, interneurons play a vital role in
modulating neuronal excitability and the generation of
temporal synchrony and oscillation among networks of
glutamatergic neurons. This role is depicted in an elo-
quent analogy by Di Cristo
[209] ‘to compare interneuron
function to the music director of a symphony orchestra,
who structures and coordinates the overall musical per-
formance. Without proper direction, the ensemble can-
not produce the right melody’. Dysfunction in GABA
neurotransmission is believed to be the aetiological basis
for a variety of neuropsychiatric disorders such as schizo-
phrenia, autism spectrum disorders, epilepsy and mood
disorders
[210–214] . This is evidenced by either loss of
interneuron numbers, calcium-binding protein charac-
teristics or alterations in synaptic receptors.
In simplistic terms there are 4 possible explanations
for a los s in GABA function in a d ise ased b rain. First, loss
of a precursor population would significantly reduce the
number of interneurons and, depending on the precur-
sor, may reduce these numbers in a subtype-specific
manner. Second, perturbations in signa lling mechanisms
regulating migration, lamination or differentiation will
reduce the number and function of integrated interneu-
rons. Third, interneurons may locate in the correct lami-
nar position at birth but become abnormal as maturation
proceeds. This reflects the protracted development of
GABA circuits occurring over the first two decades of life
[215] . Fourth, input of extrinsic fibre systems that con-
tinue until the early adult period, such as the dopaminer-
gic afferents, may develop abnormally and delay or pre-
vent interneuron maturation
[216] . We will present the
following discussion from an embryonic perspective and
ref lect on abnorma l interneuron lamination in relat ion to
signalling pathways we have described previously to be
involved with migration.
We have only just begun to appreciate the influence of
pyramidal neurons on interneuron development and the
link between genes regulating migration of both neurons.
The genetic analysis of human brain malformations
has identified mutations in 2 genes, Lis1 (also known as
PAFAH1

1 ) and Dcx , which result in a pyramidal migra-
tory disturbance known as type 1 lissencephaly, literally
meaning ‘smooth brain’
[217] . This condition is charac-
terized by a 4-layered cortex, with no obvious relation-
ship to the normal 6 layers, in addition to gyral abnor-
malities that present as a smooth exterior. Historically,
mutations in Lis1 and Dcx are associated with abnormal
pyramidal neuron migration, but more recently these
proteins have been associated with interneuron migra-
tion in rodents
[10 6 , 107] . The investigation of interneu-
ron defects in several human cases of agyria has revealed
a substantial reduction in the number of cortical, but not
brain stem and cerebellum interneurons
[218] . A signifi-
cant reduction in the number of CR-positive interneu-
rons is also not ed i n Mi ller-Dieke r sy ndr ome ( LIS1 muta-
tion)
[219] . Human mutations in the transcription factor
Arx , which is necessary for the Dlx-dependent promotion
of interneuron migration, are associated with neurologi-
cal disorders including lissencephaly, mental retardation
and epilepsy (X-linked lissencephaly associated with ab-
normal genitalia, XLAG syndrome). These conditions
display aberrant migration and differentiation of inter-
neurons
[220] , and many of the neurological phenotypes
ob se rve d i n pat ie nts c an be at tr ib uted to inte rn eu ron dy s-
function.
A deficit in GABA transmission is among the most
consistent findings in schizophrenia patients, and these
exhibit a degree of interneuron subtype specificity. A
number of detailed studies on post-mortem tissue have
revealed a decrease in PV-positive interneurons
[221, 222]
or a global decrease in GAD67 in the dorsal lateral pre-
frontal cortex
[223–225] . It remains unclear if particular
subtypes are more vulnerable in a schizophrenic brain,
and one line of evidence proposes an increased suscepti-
bility of fast-spiking PV-positive interneurons to the re-
dox dysfunction exhibited in a schizophrenic brain
[226] .
Moreover, to further characterize changes in the dorsal
lateral prefrontal cortex, a recent study has revealed lam-
ina-specific alterations in the GABA
A ␣ 1 - and  2 -recep-
tor subunits expressed by interneurons
[224] . This places
emphasis on the impairment of microcircuits rather than
global cortical circuits as a causal factor in disease pro-
gression.
The identification of susceptible genes by association
and gene linkage studies represent a major advance in in-
vestigating the aetiology of schizophrenia. One candidate
gene, NRG1 with its receptor ErbB4 , has reproducibly
transpired as being a candidate gene across differing eth-
nic groups
[151–155] . The rodent studies previously de-
scribed have shown a role for NRG1 during migration,
where type III regulates interneurons locally in the GE,
whereas type I and II signal from the cortex and promote
Migration and Lamination of Cortical
Interneurons
Neurosignals 2012;20:164–185
179
migration. ErbB4 is expressed in interneurons [148, 227]
and analysis of the ErbB4 knockout mouse shows a re-
duction of 50 and 30% of the cortical and hippocampal
interneurons, respectively
[14 6, 228] . Interestingly, in the
adult hippocampus there was a selective loss of interneu-
rons positive for PV and neuronal nitric oxide synthase,
but not SST-positive interneurons which have negligible
levels of ErbB4
[229] . From a developmental perspective,
all 3 interneurons are generated in the MGE; however,
NRG1 is required for the survival of only particular sub-
types that are also absent in the human condition.
Concluding Remarks
Our current understanding of the cellular and molec-
ular mechanisms involved in the migration and specifi-
cation of interneurons is based on decades of research.
Together with advances in new technologies, like genetic
fate mapping (for the identification of the multiple inter-
neuron subtypes) and high-resolution in vivo imaging,
there is great promise to enhance our understanding of
interneuron development. In particular, researchers are
starting to tackle the intricate issues, such as the influ-
ence exerted by pyramidal neurons over different facets
of interneuron migration. Questions relating to interneu-
ron lamination, starting with the switch from a tangen-
tial to a radial mode of migration, to the subtype-specif-
ic positioning of the interneurons with their pyramidal
counterparts, are beginning to be addressed. In the years
to come, characterization of changes in specific subclass-
es of interneurons in schizophrenia and other psychiatric
disorders will provide important insights into the ob-
served GABAergic dysfunction. Moreover, the evolution-
ary adaptation of distinct interneuron origins in humans,
as well as the existence of additional subtypes, may help
to elucidate the potential causes of many neurological
conditions. Although simultaneous studies in rodents
disclose comparable cues required for human interneu-
ron development, we must bear in mind that the genesis
of subtypes specific to higher primates may not be imi-
tated in the rodent model. Thus, like the interneurons
themselves, although we have travelled a long way in our
journey to decipher the complexities of interneuron de-
velopment, the path is still long, and there is still much to
be learned and ultimately gained.
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