Article

Selemon LD. A role for synaptic plasticity in the adolescent development of executive function. Transl Psychiatry 3: e238

Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA.
Translational Psychiatry (Impact Factor: 5.62). 03/2013; 3(3):e238. DOI: 10.1038/tp.2013.7
Source: PubMed

ABSTRACT

Adolescent brain maturation is characterized by the emergence of executive function mediated by the prefrontal cortex, e.g., goal planning, inhibition of impulsive behavior and set shifting. Synaptic pruning of excitatory contacts is the signature morphologic event of late brain maturation during adolescence. Mounting evidence suggests that glutamate receptor-mediated synaptic plasticity, in particular long term depression (LTD), is important for elimination of synaptic contacts in brain development. This review examines the possibility (1) that LTD mechanisms are enhanced in the prefrontal cortex during adolescence due to ongoing synaptic pruning in this late developing cortex and (2) that enhanced synaptic plasticity in the prefrontal cortex represents a key molecular substrate underlying the critical period for maturation of executive function. Molecular sites of interaction between environmental factors, such as alcohol and stress, and glutamate receptor mediated plasticity are considered. The accentuated negative impact of these factors during adolescence may be due in part to interference with LTD mechanisms that refine prefrontal cortical circuitry and when disrupted derail normal maturation of executive function. Diminished prefrontal cortical control over risk-taking behavior could further exacerbate negative outcomes associated with these behaviors, as for example addiction and depression. Greater insight into the neurobiology of the adolescent brain is needed to fully understand the molecular basis for heightened vulnerability during adolescence to the injurious effects of substance abuse and stress.

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Available from: Lynn Selemon, Jul 24, 2014
FEATURE REVIEW
A role for synaptic plasticity in the adolescent
development of executive function
LD Selemon
Adolescent brain maturation is characterized by the emergence of executive function mediated by the prefrontal cortex, e.g., goal
planning, inhibition of impulsive behavior and set shifting. Synaptic pruning of excitatory cont acts is the signature morphologic
event of late brain maturation during adolescence. Mounting evidence suggests that glutamate receptor-mediated synaptic
plasticity, in particular long term depression (LTD), is important for elimination of synaptic contacts in brain development. This
review examines the possibility (1) that LTD mechanisms are enhanced in the prefrontal cortex during adolescence due to
ongoing synaptic p runing in this late dev eloping cortex and (2) that enhanced synaptic plasticity in the prefrontal cortex
represents a key molecular substrate underlying the critical period for maturation of executive function. Molecular sites of
interaction between environmental factors, such as alcohol and str ess, and glutamate receptor mediated plasticity are
considered. The accentuated negative impact of these factors during adolescence may be due in part to interference with LTD
mechanisms that refine prefrontal cortical circuitry and when disrupted derail normal maturation of executive function.
Diminished prefrontal cortical control over risk-taking behavior could further exacerbate negative outcomes associated with
these behaviors, as for example addiction and depression. Greater insight into the neurobiology of the adolescent brain is
needed to fully understand the molecular basis for heightened vulnerability during adolescence to the injurious effects of
substance abuse and stress.
Translational Psychiatry (2013) 3, e238; doi:10.1038/tp.2013.7; published online 5 March 2013
Adolescent development of executive function
Adolescence is rather inexactly defined as the period
beginning with the onset of puberty and ending with the
shouldering of adult responsibilities.
1
It is a time of increased
propensity to engage in risky behaviors that include experi-
mentation with alcohol, tobacco, drugs and sexual behavior.
Dahl
1
has called the adolescent brain a ‘natural tinderbox’
because gonadal hormones are actively stimulating affective
and appetitive behaviors, such as sexual drive, increased
emotional intensity, and risk taking, yet the brain systems that
regulate and moderate these emotional and appetitive urges
are not yet mature.
The prefrontal cortex (PFC) mediates executive functions, i.e.,
internally guided behavior , goal planning, and impulse control,
that form the essence of ratio nal thinking and serve to counte r
appetitive urges and check risk-taking behavior.
2,3
The PFC is
the last brain region to mature,
4–7
and therefore not surprisingly
the frontal lobe capacity for internally guided behavior, working
memory, and organizational skills do not reach full adult
functional capacity until mid to late adolescence.
8–12
Crews et al.
13
have drawn parallels between adolescence
and early sensory critical periods, which are dependent on
plasticity of developing sensory connectivity and allow for
environmental (sensory) modulation of maturing sensory
connections. Specifically, they have suggested that in
adolescence PFC circuitry may be endowed with similar
plasticity and responsiveness to environmental factors, and
as a consequence with heightened vulnerability to the
detrimental effects of substance abuse and stress.
13
This review examines the literature on adolescent develop-
ment across species and focuses on the role that glutamate-
receptor mediated plasticity may play in maturation of PFC
circuitry in adolescence. It is postulated that adolescence
represents a phase of increased activity of long term
depression (LTD) mechanisms that predispose to synaptic
elimination and further that termination of this LTD-permissive
phase marks the transition to adulthood. Finally, consideration
is given to the possibility that greater vulnerability to
substances of abuse and stress may represent an interaction
between these environmental factors and the LTD mechan-
isms of plasticity that are accentuated during adolescence.
The hypothesis put forward in this review, while speculative, is
intended to spark further research into possible molecular
mechanisms associated with adolescent development of the
PFC. Certainly synaptic plasticity has been studied much less
extensively in the PFC than in the hippocampus; nonetheless,
mounting evidence suggests that both long term potentiation
(LTP) and LTD play an important role in cognitive functioning
mediated by the PFC and perhaps when disturbed in diseases
related to malfunction of this cortex.
14
Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA
Correspondence: Dr LD Selemon, Department of Neurobiology, PO Box 208001, New Haven, CT 06520-8001, USA. E-mail: ldselemon@aol.com
Received 4 September 2012; revised 15 Decemeber 2012; accepted 3 January 2013
Keywords: alcohol; depression; dopamine; long term depression (LTD); prefrontal cortex; substance abuse
Citation: Transl Psychiatry (2013) 3, e238; doi:10.1038/tp.2013.7
&
2013 Macmillan Publishers Limited All rights reserved 2158-3188/13
www.nature.com/tp
Page 1
Preadolescent development and sensory critical periods
The specificity and topography of brain wiring are not entirely
genetically preprogrammed but instead established via
dynamic processes occurring in the developing brain.
Adolescence represents the final epoch in a series of
developmental stages that transform the immature brain into
its adult form. In order to fully understand adolescent
development, it is important to appreciate how it differs from
earlier preadolescent maturation.
The developmental mechanisms that account for major
remodeling of connectivity occur before the onset of adoles-
cence, i.e., before postnatal day 28 (PD28) in rodents, 9
months in cats, and 3 years in non-human primates
15–17
and
include prominent degeneration of neurons and axons.
18,19
Indeed, the immature mammalian brain is distinguished from
its adult counterpart by the presence of connections between
brain areas that are not interconnected in the mature brain and
by overlap of terminal fields that are segregated in the adult
brain. For example, in the newborn hamsters and rats,
uncrossed retinocollicular projections, i.e. from the retina to
the ipsilateral superior colliculus (SC), not only occupy a much
expanded territory in the SC relative to that of the adult brain
but also originate from nasal as well as temporal retinal
ganglion cells.
20–22
Retraction of the terminal projections is
associated with loss of these nasal, ipsilaterally-projecting
ganglion cells.
22
More generally, in the central nervous
system overproduction of neurons with ensuing neuronal
death is a common mechanism employed by the developing
brain to ensure that the appropriate balance of projection and
receptive neurons is attained.
19,23–25
A second, pervasive form of degeneration in the developing
brain is degeneration limited to axonal connections leaving the
neurons of origin intact. For instance, in the central nervous
system, cortical callosal projections that are widespread in
kittens and young rats are constricted to the adult patterning
by retraction of callosal axons without cell loss.
26–28
Quanti-
tative analysis of axon number in major tracts underscores the
magnitude of this form of degeneration as the number of
axons in the young non-human primate brain ranges from
twice (optic tract) to 3.5 times (corpus callosum) the number in
the adult brain.
29–31
Both forms of degeneration, involving loss
of neurons or loss of axons, necessarily are associated with
dissolution of established synapses.
32
However, these early
developmental events are occurring at a time when, overall,
synapses are increasing in density.
33–38
The classic example
or early connectional remodeling, that of reduction of
polyneuronal input on a single muscle fiber to a single axon,
illustrates how synaptic number may increase as the surviving
single axon sprouts a much more elaborate terminal
plexus.
18,39
Likewise, in the central nervous system regres-
sion of inappropriate synapses is more than compensated by
growth and expansion of appropriate terminal fields.
40
A wealth of evidence has established that reorganization of
connections throughout the brain is activity dependent and
therefore mediated by a Hebbian mechanism.
41–45
Although
normal regression of connections in the visual system can
proceed in the absence of visual input
41
there exists a period
of plasticity during postnatal development that permits
rewiring in response to altered sensory environments.
43,46,47
It is noteworthy that critical periods for sensory plasticity occur
in the same preadolescent period in which remodeling of
connectivity occurs.
34,48,49
Adolescence: synaptic elimination and excitatory/
inhibitory balance
The maturational event most consistently linked to the
adolescent stage of development is reduction of synaptic
density or ‘synaptic pruning.’ Quantitative analyses of
synapses in the non-human primate uncovered a synchronous
increase in synaptic density in multiple cortical areas that
peaks during the postnatal 3rd month, declines slowly (10%)
untilB2 years of age with a steeper decline (40%) occurring
between 2.7 and 5 years (adulthood).
35–38
In the human cortex
the timing of peak synaptic density is staggered in different
regions, but the basic pattern of peak synaptic density in early
childhood followed by robust synapse elimination throughout
early (auditory cortex) or mid-adolescence (PFC) is in basic
agreement with non-human primate studies.
4,50
More recent
data have established that synapse elimination in humans
does not end in adolescence but continues at a lower rate into
early adulthood.
51
In addition, in human cortex the synaptic
related proteins synaptophysin and postsynaptic density
protein-95 (PSD-95) show similar patterns of peak in childhood
and decline through adolescence,
52
though it should be noted
that a recent study found increasing concentrations of
synaptic–related molecules throughout the adolescent
epoch.
53
Nonetheless, most evidence points to synaptic
pruning as the signature late maturational process associated
with adolescence. Other species have been studied less
extensively but exhibit a comparable pattern. Peak synaptic
density was observed by the 7th postnatal week in the cat.
34
In
rat, recent data suggest that peak spine density in the PFC is
present at PD31 with spine density decreasing thereafter until
PD 57 or PD60, i.e., early adulthood.
33
Synaptic elimination in adolescence is widely thought to
account for the decline in gray matter volume detected via
longitudinal magnetic resonance imaging (MRI) of human
subjects. Although reduction of synaptic connectivity might be
accompanied by retraction of glial and neuronal processes,
elimination of neuronal cell bodies occurs much earlier in
development.
54
One of the first longitudinal MRI studies of
human subjects detected divergent developmental growth
patterns in gray and white matter volumes: white matter
volume increased linearly until approximately age 22 whereas
cortical gray matter volume in the frontal and parietal lobes
peaked just prior to adolescence (B10–12 years) and then
declined to adult volumes.
5
Cross-sectional studies of
children and adolescents, including one recent large multi-
center study, also show opposing patterns for gray and white
matter.
55–57
Interestingly, changing cortical volumes over this
age range are most prominent in the frontal and parietal
lobes.
8,58,59
Indeed, a recent study indicates that there is a
progression in which higher cortical association areas like the
PFC are last to show reduction of gray matter volume.
7
The functional significance of synaptic elimination during
adolescence, though still enigmatic, probably involves adjust-
ment of the excitatory/inhibitory balance on individual neurons
Synaptic plasticity in adolescent development
LD Selemon
2
Translational Psychiatry
Page 2
and within networks. The main argument in support of this
hypothesis stems from the specificity of the loss: excitatory
synapses are selectively degenerated whereas inhibitory
synapses are spared.
35,37
Even loss of chandelier axon
boutons in the PFC, a finding that was originally interpreted as
loss of inhibitory synapses,
60
now supports the elimination of
excitatory input in light of new physiologic data.
61
Further-
more, recent evidence has established that D2 dopamine
receptors on interneurons undergo a profound maturational
change during adolescence.
62–64
Prior to adolescence, D2
stimulation elicits either no effect or only weak inhibition on
interneurons. However, in adult animals stimulation of D2
receptors is strongly excitatory and therefore results in robust
firing of interneurons and potent inhibition of their pyramidal
cell targets. As a result, inhibition gains a position of
ascendency in adolescence via increased dopamine-
mediated firing of interneurons as well as a relative gain in
inhibitory/excitatory synapse ratio. In the PFC, neurophysio-
logic studies have established a critical role for inhibitory
synapses in mediating information flow through local net-
works.
65,66
Moreover, fast-spiking interneurons mediate
gamma oscillations which are essential to cortical computation
in many areas of the cortex and to cognitive processing in the
PFC.
67,68
Thus, the correct balance of inhibition and excitation
seems to be critical for normative executive function, and
conversely, disturbance of this balance is thought to be a
fundamental component of psychiatric illness.
69,70
Molecular mechanisms associated with synaptic
stabilization and synaptic pruning
Synapse stabilization and synapse elimination are primary
players in the maturational processes associated with
preadolescent and adolescent development. The transition
of nascent synapses into mature synapses represents the first
step in synapse stabilization. N-methyl-D-aspartate receptors
(NMDAR) are localized very early to the postsynaptic
membrane, but transition to a more mature synapse state is
characterized by recruitment of alpha-amino-3-hydroxy-5-
methyl-4-isoxazole propionic acid receptors (AMPAR) to the
synapse.
71–74
Expression of AMPARs on the postsynaptic
membrane is induced by NMDAR-mediated long term
potentiation (LTP), the same mechanism originally described
in hippocampus for learning and memory.
73–76
A second
NMDAR-mediated process, LTD, results when afferent
stimulation fails to activate a target neuron.
76
In many
respects LTP and LTD are opposite processes although they
engage distinct intracellular signaling mechanisms.
77–80
Essentially stimulation of NMDARs can induce activity-
dependent strengthening of synapses via LTP or weakening
via LTD, and AMPAR insertion or removal from the
postsynaptic membrane is the conduit for this change in
synaptic strength.
81,82
Importantly, LTP and LTD do not just
strengthen or weaken synaptic connections (short term
plasticity) but actually trigger the addition or loss of synapses
(long term plasticity) even in the adult brain.
83–92
Well before the role of NMDAR-mediated LTP in
establishing mature synaptic connections was recognized,
Constantine-Paton et al.
44
postulated that activity-dependent
remodeling of connectivity in the developing brain might be
mediated by NMDARs because these receptors are perfectly
suited to detection of synchronized pre- and postsynaptic
activation. Growing evidence now supports the idea that LTP
and LTD are required for generation of whisker barrel field
maps in the primary somatosensory cortex and ocular
dominance columns in the primary visual cortex, both
involving reorganization of thalamic inputs to layer 4.
49,93–96
In development, as in learning and memory, plasticity is
bidirectional, i.e., synchronized activity of afferent inputs
may trigger LTP and resulting synapse maturation and
stabilization; conversely, asynchronous activity may diminish
synaptic strength via LTD and predispose the synapse to
elimination.
97
Recently, changes in the NMDAR have been linked to
critical periods of early developmental plasticity. NMDAR
subunit composition shifts from NR2B predominant to NR2A
prevalent forms in early development in the visual and
somatosensory cortices.
98–100
Moreover, the shift in NR2B
to NR2A shows a rough correspondence to critical periods for
sensory plasticity: the beginning of the critical period is
marked by an increase in NR2A expression, and the end of the
critical period is associated with a decrease in NR2B
expression.
100,101
Importantly, the switch is not locked to a
specific age but in fact can be delayed by sensory deprivation,
suggesting that it is controlled by activity.
93,102–105
In turn, the
changeover from NR2B to NR2A receptor subtypes controls
the sensitivity of these connections to stimulation by
NMDARs. For example, in the primary visual cortex of the
ferret, NR2B levels are already high at eye opening and
decline in layer 4 at the end of the critical period for plasticity of
ocular dominance columns but remain high in layer 2/3.
106
Correspondingly, physiologic studies in the cat visual cortex
have shown that cortical layer 4 neurons, but not layer 2/3
cells, exhibit reduced sensitivity of visual and spontaneous
activity to an NMDAR antagonist at the end of the critical
period.
107
Together these findings suggest that the switch
from NR2B to NR2A dominated receptors terminates the
critical period of experience-dependent plasticity for establish-
ment of ocular dominance columns in the visual cortex.
NMDAR-mediated LTP and LTD may a lso constitute the
molecular underpinnings for adolescent synaptic pruning, albeit
with greater emphasis on LTD and synaptic elimination. How
could the same mechanism account for two very different
developmental processes? Perhaps the period of adolescence
corresponds to a widespread shift in the balance of LTP/LTD
mechanisms and a corresponding prevalence of synaptic
elimination over synaptic addition. In rat hippocampal slices,
an increased NR2A/NR2B ratio has been linked to decreased
spine motility and increased synaptic stabilization, suggesting a
role in the NMDAR subunit composition in halting synaptogen-
esis.
108
Furthermore, the NR2A state is less conducive to LTP.
This is because calcium/calmodulin-dependent protein kinase II
(CaMKII), which has a well established role in LTP,
109,110
binds
preferentially to the NR2B subunit.
110–112
Accordingly, NR2B
expression on the postsynaptic membrane has been shown to
be necessary for LTP induction, while a role for NR2A in LTP is
not well established.
113–115
Moreover, NR2A expression is
enhanced by ligand binding to NMDARs and therefore is
activity-modulated whereas NR2B expression is not dependent
on previous activity.
116
The NR2A subunit is therefore thought to
Synaptic plasticity in adolescent development
LD Selemon
3
Translational Psychiatry
Page 3
be responsible for metaplasticity of synapses, i.e., a change in
the likelihood of subsequent synaptic plasticity.
117,118
With age
and activity, NR2A subunits become incorporated into the
postsynaptic membrane, replacing NR2B subunits.
116
The
resulting increased NR2A/NR2B ratio translates into a higher
threshold for induction of LTP and conversely a state that is
more favorable for induction of LTD.
118,119
The role of plasticity in the neocortex is not as well
established as in the hippocampus. However, NMDAR-
mediated LTP and LTD have been described in the visual
neocortex
120
and at multiple synapses in the PFC.
121–123
Notably, LTD mediated through metabotropic glutamate
receptors (mGluRs) has emerged as a major alterative to
NMDAR-mediated LTD in widespread areas of the brain
124–126
and therefore deserves consideration as a possible molecular
basis for synaptic pruning in the PFC. In this regard, mGluR
plasticity has been described at the thalamocortical synapse in
the somatosensory cortex,
127
perhaps indicating that this form
of plasticity is also present at the mediodorsal thalamic
synapses in the PFC. However, at the thalamocortical synapse,
mGluR LTD acts presynaptically to decrease transmitter
release and depress synaptic activity.
127
Such a mechanism
would be unlikely to result in synapse loss and spine involution
and therefore would not be a strong candidate for LTD-
facilitated synaptic pruning during adolescence. Furthermore,
mGluR LTD at postsynaptic sites in the hippocampus has been
associated with large spines containing an abundance of
AMPAR.
128
Unlike the hippocampus where large mushroom
spines are in the majority, thin, filopodial spines predominate in
the PFC.
129
Thus, strong evidence for mGluR in plasticity
related to PFC synaptic pruning is presently lacking; none-
theless, possible involvement of mGLuR-mediated LTD in
prefrontal adolescent maturation cannot be discounted.
Many questions remain to be answered about the role of
metaplasticity in the PFC as well. As the NR2A subtype
promotes a LTD-receptive state in the synapse and LTD is
associated with synaptic elimination, it would be interesting to
know whether and when the NR2B to NR2A switch occurs in
the PFC and how it relates to the synaptic pruning that refines
connectivity associated with cognitive control of behavior. If
the LTD-receptive state is a hallmark of adolescent develop-
ment, a reasonable presumption is that there exists an
additional molecular switch that greatly curtails the LTD-
receptive state of adolescence into the much less receptive
state of adulthood. This switch, although presently unidenti-
fied, would transform the synapse into a state that is less
receptive to alterations in AMPAR expression on the
postsynaptic membrane. Given that synaptic pruning con-
tinues into early adulthood albeit at a lower level than that of
adolescence,
33,51
it seems likely that the transition phase is
gradual rather than abrupt resulting in a much less plastic
state by the end of the third decade in humans.
Adolescence development of cognitive function and
synaptic plasticity
Executive functions governed by the PFC exhibit a prolonged
period of maturation reaching fulfillment only in late
adolescence.
11,130
Volumetric changes occurring during
adolescence have been correlated with improved cognitive
performance, e.g., verbal and spatial memory performance is
positively correlated with gray matter thinning in the frontal
lobes.
6
General intelligence has also been shown to bear a
relationship to the trajectory of frontal cortical gray matter
thinning, such that subjects with superior intelligence show a
robust early adolescent increase in gray matter volume
followed by equally robust thinning during later adoles-
cence.
131
However, too much cortical thinning during adoles-
cence has been associated with diseased states such as
Attention Deficit Hyperactivity Disorder (ADHD).
132
Thus,
there is an optimal level of synaptic pruning that is essential to
normal development of adult cognitive function.
One recent study addressed the role of AMPAR expression
and LTD in the development of PFC function in the mouse.
Vazdarjanova et al.
133
utilized a transgenic mouse that over-
expresses calcyon, a protein which mediates activity-depen-
dent AMPAR internalization, and found that calcyon over-
expression over the lifetime of the mouse resulted in marked
impairment of contextual fear extinction (CFE) and working
memory capacity, both dependent on normal PFC function.
Most relevant to this discussion, adolescence was the critical
period for production of these deficits. When over-expression
was silenced specifically during the adolescent epoch, normal
CFE function was rescued.
133
One possible explanation for
these findings is that AMPAR internalization and associated
functions like LTD are more sensitive to regulation during
adolescence and this regulation is turned off, or at least
greatly diminished, in the adult brain. Whether overactive LTD
during adolescence translates into altered synaptic number in
the PFC or elsewhere is currently not known. However, it is
interesting that upregulated calcyon expression has been
found in schizophrenia, a neurodevelopmental disease in
which PFC gray matter deficits are prominent.
134–136
In the PFC, synaptic plasticity is highly modulated by
dopamine receptor, especially the D1 receptor.
14,122,137
This
is not surprising since D1 receptor stimulation has been shown
to trigger phosphorylation of AMPAR, which in turn promotes
trafficking of these receptors to the external membrane.
138,139
The D1 receptor is therefore strategically positioned to effect
changes in AMPAR synaptic expression and ultimately in
synaptic strength and/or number. In the adult non-human
primate, long term sensitizing regimens of amphetamine
decrease spine density on pyramidal cells in the PFC and
have detrimental effects on working memory performance.
140
Moreover, these effects seem to be due to changes at the D1
receptor because both cognitive and morphologic effects on
PFC pyramidal neurons can be reversed by long term
treatment with a D1 antagonist.
141
If AMPAR-mediated LTD
expression is in a state of greater sensitivity to modulation in
adolescence, then D1 receptor-stimulated interference with this
mechanism could be magnified during adolescence resulting in
exaggerated consequences at the synapse. Other known
modulators of synaptic plasticity, e.g. D2,
139
muscarinic,
142
and
cannabinoid
143
receptors, might have similarly increased
potency during the adolescent period.
Adolescence vulnerability to environmental factors
Adolescence has been described as a period of accentuated
opportunity and of enhanced vulnerability.
1
It has long been
recognized that early onset of substance abuse is associated
Synaptic plasticity in adolescent development
LD Selemon
4
Translational Psychiatry
Page 4
with greater propensity for problem drug use later in life.
144–147
In
recent years, the period of adolescent plasticity has been shown
to temporally correlate with the time of greatest vulnerability to
addiction.
148
Some have postulated that addiction conscripts the
learning and memory pathways in a maladaptive fashion,
149,150
but the question of why addiction is more devastating in
adolescence than in adulthood remains unanswered. Adoles-
cence is also associated with onset of mental illness, as for
example depression rates rise in adolescence especially for
females,
151
and the prodromal phase of psychosis, including
early onset schizophrenia, surfaces during the adolescent
window.
152
Despite the fact that adolescents are bigger and
stronger than younger children, mortality rates increase more
than 200% from childhood mainly due to accidents, suicide,
substance abuse, and eating disorders.
1
One of the most studied environmental effects in adoles-
cence is alcohol abuse. In adults, brain toxicity has been
documented as a consequence of chronic alcohol abuse:
cortical gray matter thinning is most prominent in the PFC
153
and associated with changes in neuronal and glia density in
both the orbitofrontal
154
and superior frontal cortices.
155
Alarmingly, the detrimental effects of alcohol consumption
seem to be magnified in adolescence. Studies in human
subjects have shown that impairment of memory function is
more pronounced following even acute exposure to alcohol in
younger (ages 21–24) than in older (ages 25–29) subjects.
156
In adolescent rats, ethanol administration selectively impairs
spatial memory whereas adult rats are unaffected by the same
doses.
157
Moreover, ethanol consumption in rats that simu-
lates binge drinking results in more widespread pathology in
adolescent animals than in adults.
158
The basis of the enhanced vulnerability to alcohol in
adolescence is undoubtedly complex and involves interaction
with multiple neurotransmitter systems.
159
With regard to
neuroplasticity, there are well documented effects of alcohol
on the glutamate system. Acutely, ethanol inhibits NMDAR
neurotransmission whereas long term exposure results in
homeostatic upregulation of NMDAR signaling.
159,160
There is
also growing evidence to suggest that ethanol has a greater
effect on glutamate neurotransmission during adolescence
than in later life. Ethanol exposure at low doses in adolescent
rats is associated with inhibition of NMDAR-mediated EPSCs
in the CA1 region of the hippocampus while high doses are
required to inhibit EPSCs in adults.
161
Ethanol also blocks
LTP in CA1 neurons of the hippocampus in adolescent but not
adult rats.
162
Thus, even acute alcohol consumption in
adolescence could disrupt mechanisms of Hebbian plasticity,
and more chronic alcohol consumption in adolescence may
induce homeostatic upregulation of glutamate neurotransmis-
sion that could result in long term changes in synapse number
and dendritic spine morphology.
160
Homeostatic regulation of
synaptic activity, i.e., increases or decreases synaptic scaling
across the whole population of synapses, is also thought to be
mediated by increased or decreased expression of AMPAR
receptors on the post-synaptic membrane.
163
This suggests a
potential site of interaction between developmental plasticity
and homeostatic plasticity since both involve trafficking of
AMPARs. Furthermore, sites of homeostatic plasticity corre-
late with lamina that exhibit plasticity during critical periods in
the visual and somatosensory cortices, suggesting a possible
mechanism for heightened vulnerability of selected circuitry
during different phases of development.
163
If synaptic
plasticity in adolescence is primarily occurring in the neural
circuitry that mediates executive processing, then disruption
of synaptic plasticity at this time might result in enduring
deficits in control of emotion, logical thinking and inhibition of
impulsivity. In turn this lack of executive control could
exacerbate the addictive tendencies and result in more
severe alcoholism.
The adolescent brain is also more responsive to stress than
the adult brain
164
and as a consequence may be more
vulnerable to depression.
151
Analogous to the manner in
which alcohol has age-specific effects that may be depend on
which regions of the brain are most plastic, a recent study has
shown that the effects of sexual abuse, presumably the stress
associated with the abuse, produces different brain pathology
at childhood and adolescent ages.
165
Notably, frontal gray
matter volume deficits were most pronounced in adult
subjects who experienced sexual abuse at ages 14–16.
165
The neural pathways that mediate and modulate the
stressful effects on cognitive function in the PFC involve
monoamine signaling.
164
Given the prominence of dopamine
neurotransmission in mediating stress, the development of
dopamine innervation of the PFC during late maturation might
provide insight into the enhanced sensitivity to stress at this
age. In the non-human primate, dopamine innervation of the
middle PFC layers peaks near the onset of puberty and then
decreases rapidly to adult levels while innervation of other
layers is stable throughout the postnatal period.
166
D1
receptor levels also peak and decline to adult levels around
the beginning of puberty.
167
These findings which indicate that
the adult D1 receptor pattern is reached early do not appear to
support a role for dopamine in adolescent enhancement of
plasticity. However, in rodent prefrontal cortex, cell specificity
has been observed in the distribution of D1 receptors with
pyramidal cell neurons, but not interneurons, expressing
higher levels of D1 receptors in adolescence than in
adulthood.
168
These rodent data suggest that changes in D1
receptor expression might accentuate dopamine signaling in
adolescence and thereby account for greater plasticity during
this critical period. However, a credible alternative explanation
is that the LTD-receptive state of adolescence is more
sensitive to modulators like dopamine and that critical
differences might be found in the mechanisms of glutamate
receptor-mediated synaptic plasticity in the adolescent brain
compared its adult counterpart.
Clinical considerations
Identifying the molecular basis for synaptic pruning in
adolescence could have wide ranging clinical ramifications.
If NMDA-mediated LTD were proved to underlie reduction of
connectivity, then the intracellular pathways associated with
LTD processes, including those that mediate AMPAR inter-
nalization, could be targeted to curtail excessive synaptic
pruning in diseases such as schizophrenia and ADHD.
Because the D1 receptor is a key modulator of synaptic
plasticity in the PFC and can even determine polarity of
plasticity, i.e. high dopamine levels can predispose prefrontal
synapses to LTD over LTP,
137
treatment with dopaminergic
Synaptic plasticity in adolescent development
LD Selemon
5
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Page 5
antagonists or drugs that target intracellular dopamine
signaling might also be useful in decreasing overactive LTD
mechanisms. Along these same lines, drugs that impact the
D1 receptor or its signaling pathways could ameliorate the
impact of stress on the adolescent brain of individuals at risk
for depression. Likewise, the involvement of glutamate
receptors, including mGluRs,
126
in drug and alcohol addiction
raises the possibility that pharmacologic targeting of gluta-
mate signaling might have the potential to diminish the long
term consequences of substance abuse in adolescence. In
the same manner that the discovery of aberrant mGluR5
mechanisms in Fragile X syndrome has spawned new
therapeutic approaches for treating this disease,
169–171
greater insight into the molecular substrates of adolescent
maturation of the prefrontal cortex might lead to similar novel
drug development for disorders and environmental exposures
linked to abnormal adolescent development.
Conclusions
The adolescent epoch is a time when refinement of
connectivity establishes the proper excitatory/inhibitory bal-
ance in the PFC, and it is a critical period for normal
maturation of executive functioning. Adolescence is postu-
lated to be a time when LTD-driven synaptic pruning is
occurring at a high rate in regions that govern higher cognitive
function like the PFC. Further, the transition to adulthood is
hypothesized to be marked by changes in the synapse that
make the mature neuron less sensitive to AMPAR internaliza-
tion, less likely to undergo LTD and thus less likely to undergo
retraction of synaptic contacts.
Conflict of interest
The author declares no conflict of interest.
Acknowledgements
. I thank Dr Keith Young for his pre-submission
reading of this manuscript and helpful comments.
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    • "First, some of the treatments already tested in mouse models of ASD have been able to ameliorate both cognitive and morphological alterations; moreover, a few clinical tests with humans show promising results (this is true at least for the use of mGluR5 regulators in FXS or PI3K activators for Rett syndrome treatment). On the other hand, most of the cellular mechanisms regulating neuronal plasticity during development are also present later in adolescence and adulthood [145, 146]. The neuropathological features of ASD include altered cellular size and synaptic growth, synaptic plasticity failure, changes in synaptic proteins, dendritic spine dysmorphology and abnormal synaptic homeostasis [3, 147, 148]. "
    [Show abstract] [Hide abstract] ABSTRACT: This review is focused in PI3K’s involvement in two widespread mental disorders: Autism and Schizophrenia. A large body of evidence points to synaptic dysfunction as a cause of these diseases, either during the initial phases of brain synaptic circuit’s development or later modulating synaptic function and plasticity. Autism related disorders and Schizophrenia are complex genetic conditions in which the identification of gene markers has proved difficult, although the existence of single-gene mutations with a high prevalence in both diseases offers insight into the role of the PI3K signaling pathway. In the brain, components of the PI3K pathway regulate synaptic formation and plasticity; thus, disruption of this pathway leads to synapse dysfunction and pathological behaviors. Here, we recapitulate recent evidences that demonstrate the imbalance of several PI3K elements as leading causes of Autism and Schizophrenia, together with the plausible new pharmacological paths targeting this signaling pathway.
    Full-text · Article · Dec 2016
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    • "Related studies have shown evidence of age-related neurodevelopment from childhood to early adolescent in ASD (O'Hearn et al. 2008 ). EFs in this transition stage warrant investigation (Selemon, 2013). Despite extensive research of EFs in ASD, the sample sizes of most studies are relatively too small to establish a conclusion (Ozonoff et al. 2004; Barnard et al. 2008; Sumiyoshi et al. 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Impaired executive function (EF) is suggested to be one of the core features in individuals with autism spectrum disorders (ASD); however, little is known about whether the extent of worse EF in ASD than typically developing (TD) controls is age-dependent. We used age-stratified analysis to reveal this issue. Method: We assessed 111 youths with ASD (aged 12.5 ± 2.8 years, male 94.6%) and 114 age-, and sex-matched TD controls with Digit Span and four EF tasks of the Cambridge Neuropsychological Test Automated Battery (CANTAB): Spatial Span (SSP), Spatial Working Memory (SWM), Stockings of Cambridge (SOC), and Intradimensional/Extradimensional Shift Test (I/ED). Results: Compared to TD controls, youths with ASD performed poorer on the Digit Span, SWM, SOC, and I/ED tasks. The performance of all the tasks improved with age for both groups. Age-stratified analyses were conducted due to significant age × group interactions in visuospatial planning (SOC) and set-shifting (I/ED) and showed that poorer performance on these two tasks in ASD than TD controls was found only in the child (aged 8-12 years) rather than the adolescent (aged 13-18 years) group. By contrast, youths with ASD had impaired working memory, regardless of age. The increased magnitude of group difference in visuospatial planning (SOC) with increased task demands differed between the two age groups but no age moderating effect on spatial working memory. Conclusions: Our findings support deficits in visuospatial working memory and planning in youths with ASD; however, worse performance in set-shifting may only be demonstrated in children with ASD.
    Full-text · Article · Mar 2016 · Psychological Medicine
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    • "In addition, CB signaling inhibits microglia function (Walter et al., 2003 ). These two points are important because cortical pruning processes involve glial-mediated synaptic elimination and altering the excitatory/inhibitory balance is liable to disrupt the selective tagging and preserving synapses (Selemon, 2013). The impact of this indirect influence on the developing brain may be in the observations of abnormal connectivity in those who began MJ use in adolescence (Jacobus et al., 2009 ). "
    [Show abstract] [Hide abstract] ABSTRACT: Background: As the most commonly used illicit substance during early adolescence, long-term or latent effects of early adolescent marijuana use across adolescent developmental processes remain to be determined. Methods: We examined cortical thickness, gray/white matter border contrast (GWR) and local gyrification index (LGI) in 42 marijuana (MJ) users. Voxelwise regressions assessed early-onset (age <16) vs. late-onset (≥16 years-old) differences and relationships to continued use while controlling for current age and alcohol use. Results: Although groups did not differ by onset status, groups diverged in their correlations between cannabis use and cortical architecture. Among early-onset users, continued years of MJ use and current MJ consumption were associated with thicker cortex, increased GWR and decreased LGI. Late-onset users exhibited the opposite pattern. This divergence was observed in all three morphological measures in the anterior dorsolateral frontal cortex (p<.05, FWE-corrected). Conclusions: Divergent patterns between current MJ use and elements of cortical architecture were associated with early MJ use onset. Considering brain development in early adolescence, findings are consistent with disruptions in pruning. However, divergence with continued use for many years thereafter suggests altered trajectories of brain maturation during late adolescence and beyond.
    Full-text · Article · Oct 2015
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