increased in the striatum of R6/2 and
YAC128 transgenic mice. Genetic or
pharmacological interventions that block
MMP-mediated production of Htt frag-
ments therefore provide a target for
therapeutic intervention (Figure 1B). If
a selective inhibitor of MMP-10 can be
developed, then this could be tested in
patients. We showed the feasibility of
utilizing an MMP inhibitor therapeutically
in another neurodegenerative disease, in
et al., 2006). To investigate this further, it
would be of interest to produce a trans-
genic HD mouse in which the MMP-10
site is mutated, such that it cannot be
cleaved, and then to determine whether
this abolishes the disease phenotype
and pathology, similar to observations
with caspase 6. It will also be of interest
to cross MMP-10 knockout mice with
full-length transgenic mouse models of
HD. Activation of MMP-10 is known to
occur in response to histone deacetylase
7 (HDAC7) knockdown (Chang et al.,
2006); thus, another interesting approach
to achieve downregulation of MMP-10
HDAC7 in HD cells, or transgenic mice
and investigate whether this ameliorates
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Going Tubular in the Rostral Migratory Stream:
Neurons Remodel Astrocyte Tubes to Promote
Directional Migration in the Adult Brain
Tae-Yeon Eom,1Jingjun Li,1and E.S. Anton1,*
NC 27599, USA
Newly generated neuroblasts from the subventricular zone of the adult brain migrate as neuronal chains
within anetworkofastroglial tubes inthe rostralmigratory stream.This highly directed, rapidmigration chan-
nels new neurons to the olfactory bulb. In this issue of Neuron, Kaneko et al. demonstrate that migrating
neurons dynamically remodel the morphology and organization of astroglial tubes to promote long distance,
directional migration of neurons in the adult brain.
Reciprocal interactions between migrat-
ing neurons and astroglia play influential
roles in the guidance and placement of
newly generated neurons in the cerebral
cortex. During embryonic development,
migrating neurons modulate the function
of radial glial cells as neuronal migratory
guides in the neocortex (Hatten, 1985;
Rakic, 2003). In contrast, in the adult
brain, long distance neuronal migration
is thought to occur in a glial-independent
manner. In the rostral migratory stream
Neuron 67, July 29, 2010 ª2010 Elsevier Inc.
(RMS), newly generated neurons from the
subventricular zone migrate along each
their target locations in the olfactory bulb
(Wichterle et al., 1997). During this pro-
plex network of astrocyte tubes (Doetsch
and Alvarez-Buylla, 1996; Lois et al.,
astroglial tubes, whether they merely act
as barriers to prevent the dispersion of
the young neuroblasts into the surround-
ing tissue or if they actively guide or orient
the new neurons, has remained unclear.
In this issue of Neuron, Kaneko et al.
(2010) provide evidence that new neurons
may actively modulate the formation
and organization of the astrocyte tunnel
network to facilitate their directed migra-
tion in the mature brain. To explore the
impact of neuron-astroglial interactions
in directional migration in the adult brain,
they analyzed neuronal migration and
RMS organization defects in Slit1 null
mice. Previous findings demonstrated
that Slit1, a diffusible chemorepulsive
protein, is expressed by migrating neu-
rons in the RMS and may cell autono-
mously regulate their migration (Nguyen-
Ba-Charvet et al., 2004). Kaneko et al.
(2010) extend these findings by live-
imaging the migration of Slit1 deficient
neurons in brain slices and by mapping
the migratory behavior of wild-type (wt)
and Slit1?/?neurons transplanted into
either wt or Slit1?/?RMS. These studies
clearly establish that both cell-autono-
mous and non-cell-autonomous effects
of neuronal Slit1 are critical for oriented
neuronal migration in the RMS. Impor-
tantly, they noticed that the astrocyte
tube network is significantly disrupted
in Slit1?/?RMS. Astrocyte processes,
instead of orienting parallel to and sur-
rounding the migrating neuroblast chains,
were found to invade and run across
the chains of migrating neurons in the
absence of Slit1. This observation sug-
gested that neuronal Slit1 may modulate
the organization of the astrocyte tubes in
the RMS to promote oriented neuronal
migration and that disruption of this
process in the Slit1?/?RMS may be an
underlying cause of the migratory defect.
To test this, they examined the patterns
of neuron-astroglial interactions in vitro
in the absence of neuronal Slit1. Slit1?/?
neurons made irregular associations with
astroglia, resulting in altered migration.
Slit1 repelled astrocytes in vitro without
affecting their survival or proliferation.
How this chemorepellent activity of Slit1
is counterbalanced or modified during
neuron-astroglial interactions in vivo is
unclear. However, neuron or astrocyte-
specific Slit receptor perturbance assays
indicate that the neuronal Slit1 effect
is in part mediated by Slit’s receptors,
Robo2 and 3, expressed in astrocytes.
Slit1-dependent, Robo receptor signaling
in the RMS astrocytes promoted neuro-
nal migration on astrocytes in vitro and
induced changes in astrocyte morphol-
ogy (i.e., furrow-like membrane invagina-
tions) that may accommodate chains
of migrating neurons. Together, these
results support their compelling hypoth-
esis that new neuroblasts in the postnatal
brain dynamically modulate the astroglial
tunnel network along their migratory route
to promote their directional migration.
Although this study utilizes several
elegant in vitro neuron-astroglial assays
and cell-type-specific manipulation of
the Slit-Robo signaling system to demon-
stratethe influential role of new neurons in
modifying the astroglial network, further
in vivo evidence from postnatal neuronal
or astroglial-specific conditional inactiva-
tion of Slit1, Robo2, and Robo3 will be
essential to firmly establish the in vivo
relevance of this mode of neuron-glial
interactions in adult neuronal migration.
The expression of Robo receptors in
both neurons and astrocytes and the
known influence of nonneuronal Slit on
neuronal migration in the RMS (Sawa-
moto et al., 2006) support the need for
The identification of astroglial mem-
brane furrows as a significant indicator of
neurons’ ability to modify their migratory
route highlights several interesting issues
regarding their role in neuronal migration
in adult brain. Membrane deformations
of neurons have been shown to be essen-
tial for their normal migration (Guerrier
et al., 2009). The chemorepellent-like
activities of neuronal Slit1 that changed
the membrane contours of the surround-
ing astroglial cells, shown in this study,
suggest that co-coordinated membrane
deformation of both migrating neurons
and the surrounding astroglial cellular
environment are critical to promote ori-
ented neuronal migration. Whether the
Slit-Robo signaling systemissuchacoor-
dinator in the RMS remains to be deter-
mined. Further, the membrane furrows
that are induced by migrating neurons
could be simple mechanical deformations
or sites of accumulation of specific sig-
naling or adhesion complexes. Do attrac-
tive signals between astrocytes and
migrating neurons also lead to the forma-
tion of similar furrows? Do these furrows
provide any directional orientation cues
to migrating neural chains? Do they only
modulate neuronal migration or may they
also provide contact-mediated signals to
trigger the mitosis of immature neuro-
blasts in the RMS? (Lim and Alvarez-
Buylla, 1999; Menezes et al., 1995). Do
new neurons induce furrow formation
and organizational changes in RMS astro-
cytes only and not in astroglia from else-
where in the brain parenchyma? Further
ultrastructural as well as molecular char-
acterization of these astroglial furrows
will be informative in deciphering their
importance in the RMS.
New neurons, in addition to clearing the
impeding astrocyte processes away from
the path of migrating neuronal chains and
modifying the contours of the astroglial
tube membrane surfaces to fit these
moving chains, may also dynamically
modulate the overall
network (Figure S4 of Kaneko et al.). It is
attractive to speculate that this ability to
constantly modify the organization of the
tubular network of astrocytes may help
to seamlessly channel the streaming
chains of new neurons toward the olfac-
tory bulb in an efficient manner, without
creating choke points along the way.
Recent studies have also identified blood
vessels within the RMS as additional
scaffolds for chain migration of neurons
(Snapyan et al., 2009; Whitman et al.,
2009). Astroglial cells form intimate asso-
ciations with these blood vessels and
modulate the ability of the vasculature to
influence neuroblast migration (Snapyan
et al., 2009). In this context, it will be
important to understand the impact of
astroglial tube remodeling on RMS vas-
culature and its effects on neuroblast
chain migration. Such interactions might
occur via Slit1-independent mechanisms
appears to be unaffected (Figure S1 of
Kaneko et al.).
Neuron 67, July 29, 2010 ª2010 Elsevier Inc.
The idea that new neurons generated
in the mature brain can facilitate their
own migration through the complex brain
parenchyma to their proper target areas
by modifying their migratory highway to
tially significant implications. Although the
existence of rostral migratory stream-like
long distance migration in the adult
human brain remains controversial (Curtis
et al., 2007; Sanai et al., 2007), the ability
to modify the migratory route to facilitate
the targeted movement of endogenously
generated or transplanted neuroblasts will
have a significant impact on regenerative
therapeutic approaches aimed at pro-
moting functional recovery after brain
injuries. Effective functional repair strate-
gies in the adult brain depend not only
on replacement with appropriate num-
bers and types of neurons, but also
on proper migration of transplanted or
endogenously generated neurons to sites
where they are needed. Further charac-
terization of the mechanisms underlying
new neurons’ ability to modify their migra-
the mature brain will help optimize these
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Pausing to Regroup: Thalamic Gating
of Cortico-Basal Ganglia Networks
Catherine A. Thorn1and Ann M. Graybiel1,*
1McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology,
Cambridge, MA 02139, USA
How the cholinergic and dopaminergic systems of the striatum interact and how these interface with the
massive neocortical input to the striatum are classic questions of cardinal interest to neurology and psychi-
the striatum targeting its cholinergic interneurons.
Imagine you are a runner and you had to
stop at a busy intersection. From long
experience you know that it will be a while
before it is your turn to cross, so while you
wait, you start thinking about your friend
and direct your attention away from the
intersection. Finally, the walk sign comes
on, and you stop day-dreaming and start
to cross the street. Now imagine that
suddenly, a fast-moving truck honks at
you as you begin to cross—your attention
is strongly redirected now, and to avoid
being run over, you freeze on the sidewalk
and watch the truck barrel past.
What mechanisms are responsible for
redirecting your attention and interrupting
your ongoing activity—first in the subtler
case of noticing the walk sign and inter-
rupting your day-dreaming, and then in
the more dramatic freezing in response
to the horn, interrupting your run? The
intralaminar nuclei of the thalamus are
thought to be critical for this redirection
of attention, and in this issue of Neuron,
Ding et al. (2010) demonstrate cellular
mechanisms by which thalamic circuitry
may interact with cortico-basal ganglia
networks to interrupt ongoing motor
behavior and redirect attention toward
Neuron 67, July 29, 2010 ª2010 Elsevier Inc.