Available online at www.sciencedirect.com
A synaptic trek to autism
Autism spectrum disorders (ASD) are diagnosed on the basis
of three behavioral features namely deficits in social
communication, absence or delay in language, and
stereotypy. The susceptibility genes to ASD remain largely
unknown, but two major pathways are emerging. Mutations in
TSC1/TSC2, NF1, or PTEN activate the mTOR/PI3K pathway
and lead to syndromic ASD with tuberous sclerosis,
neurofibromatosis, or macrocephaly. Mutations in NLGN3/4,
SHANK3, or NRXN1 alter synaptic function and lead to mental
PI3K pathway is associated with abnormal cellular/synaptic
growth rate, whereas the NRXN–NLGN–SHANK pathway is
associated with synaptogenesis and imbalance between
excitatory and inhibitory currents. Taken together, these data
strongly suggest that abnormal synaptic homeostasis
represent a risk factor to ASD.
1Human Genetics and Cognitive Functions, Institut Pasteur, 25 rue du
Docteur Roux, 75015 Paris, France
2University Denis Diderot, Paris 7, Paris, France
Corresponding author: Bourgeron, Thomas (email@example.com)
Current Opinion in Neurobiology 2009, 19:231–234
This review comes from a themed issue on
Edited by Takao Hensch and Andrea Brand
Available online 21st June 2009
0959-4388/$ – see front matter
# 2009 Elsevier Ltd. All rights reserved.
Autismaffects about 0.7% ofchildren and ischaracterized
by deficits in social communication, absence or delay in
language, and stereotyped and repetitive behaviors.
Beyond this unifying definition, lies a spectrum of dis-
orders/conditions, ranging from severe impairments to
mild personality traits. Autism spectrum disorders
(ASD) are diagnosed before three years of age, a period
characterized by intense synaptogenesis in the human
brain . This review reports recent genetic and neuro-
biological findings that highlight two routes leading to
ASD: abnormal cellular/synaptic growth and imbalance
between inhibitory and excitatory synaptic currents.
Abnormal cellular/synaptic growth in ASD
The hypothesis that abnormal cellular/synaptic growth
may increase the risk of having ASD, was first suggested
by the recurrent observation of macrocephaly in 10–30%
of the patients with ASD [2–4]. The head circumference
may be normal at birth, but during the first four years of
life, an overgrowth of the brain is observed [5,6]. The
nature of the macrocephaly — too many neurons, glial
cells,synapses,orlargercells — remainsdifficulttoestab-
lish. However, studies on neurofibromatosis, tuberous
sclerosis, and Cowden/Lhermitte–Duclos syndromes
have provided interesting information on the link be-
tween abnormal growth rate and ASD . These genetic
syndromes associate both susceptibility to ASD and
macrocephaly and are caused by mutations in the tumor
suppressor genes NF1, TSC1/TSC2, and PTEN . In
tuberous sclerosis, mutations of TSC1/TSC2 induce cor-
tical developmental malformations called tubers. These
tubers were originally thought to be the cause of ASD
when their locations in the brain were overlapping areas
important for social communication and language. How-
ever, studies in mice showing that loss of Tsc1/Tsc2 or Pten
results in neuronal hypertrophy have led to the hypoth-
esis that susceptibility to ASD was not because of the
tubers, but to an abnormal shape and size of the neurons
Interestingly, NF1, TSC1/TSC2, and PTEN act in a
common pathway as negative effectors of the rapamy-
cin-sensitive mTOR–raptor complex (mTORC1), a
major regulator of cellular growth in mitotic cells .
Mutations are predicted to enhance the mTORC1 com-
plex, a signal activated by a sequential kinase cascade
downstream of phosphoinositide-3 kinase (PI3K) path-
way. This pathway may also be modulated by serotonin
since macrocephaly and abnormal behaviors are exacer-
bated in mice with both Pten and serotonin transporter
mutations . A stimulating hypothesis proposed by
Kelleher and Bear, suggests that the increase of the
mTOR pathway could lead to abnormal synaptic function
owing to an excess of protein synthesis at the synapse
Abnormal balance between inhibitory and
excitatory currents in ASD
The possibility that alteration of synaptic functions could
lead to ASD was first indicated by the phenotypic overlap
between autism, fragile X syndrome, and Rett syndrome
[12,13]. In addition, the key role of the excitatory/inhibi-
tory currents in ASD was further supported by the obser-
vation that 10–30% of patients with ASD have epilepsy
. The synaptic hypothesis was confirmed by the
identification of mutations affecting the postsynaptic cell
adhesion molecules Neuroligins (NLGN) in individuals
with ASD [15??,16]. At the functional level,the mutations
Current Opinion in Neurobiology 2009, 19:231–234
were found to alter the property of the NLGN to trigger
synapse formation in cultured neuronal cells . NLGN
mutations probably concern a limited number of cases
(<1% of the individuals), but following these initial
results, mutations in other synaptic proteins such as
SHANK3, NRXN1, CNTNAP2, CNTN3/4, and PCDH9/
10 were identified in patients with ASD [18–25]. Inter-
estingly, NRXN1 codes for the presynaptic binding part-
ner of NLGNs, CNTNAP2 (Caspr2) possess strong
of the postsynaptic density that binds to NLGN and
regulates the size and shape of dendritic spines .
Only limited data are available for understanding the role
of these proteins in the human brain, but studies using
neuronal cell culture and animal models have provided
crucial information. Firstly, NLGNs
enhance synapse formation in vitro [27??], but are not
required for the generation of synapses in vivo [28??].
Therefore, NLGNs may not establish synapses, but may
contribute to the activity-dependent formation of neural
circuits [29?]. Secondly, NLGNs and NRXNs are emer-
ging as central organizing molecules for excitatory gluta-
matergic and inhibitory GABAergic synapses in the
mammalian brain [30,31]. The mutant mice carrying a
R451C Nlgn3 mutation identified in two brothers with
ASD displays an increased number of GABAergic
synapses and inhibitory currents . An imbalance of
inhibition and excitation was also observed in MeCP2
knockout  and in several mice proposed as model of
autism such as the Caps2 knockout  or mice subject to
prenatal valproate treatment . Interestingly, the link
between GABA function and spine pruning has been
identified during a critical period of brain development
when individual experience is essential for the normal
development of the neuronal network . Therefore,
impaired inhibitory–excitatory balance can be manifest as
a shifted critical period for brain development  or an
alteration of sensory processing, such as reduced gamma
oscillations in FMRP knockout mice  as seen also in
ASD . Taken together, these results strongly suggest
that synapse homeostasis and specificity play an import-
ant role in the susceptibility to ASD.
Atypical neuronal networks in ASD
In the human cerebral cortex, the first synapses are
evident at the 40th day after conception. Thereafter,
the rate of synapse formation and pruning exhibit distinct
phases, the most dramatic change takes place during the
perinatal period (Figure 1). During the first three years of
life, synaptic contacts are formed, but only some will be
stabilized. This selection process represents a key step in
the cognitive development of the child. The NLGN–
NRXN–SHANK pathway is probably required during
this stabilization phase of the synapse in response to
neuronal activity. Strikingly, the role of the NLGN–
NRXN–SHANK pathway in the development of social
interaction seems to be conserved in other species.
Schematic representation of the different phases of synaptogenesis in the human brain. During the first three years of life, an excess of cell/synaptic
growth rate and inhibitory currents could increase the risk of ASD. Mutations within the mTOR/PI3K pathway lead to an excess of synaptic/cell growth.
Mutations within the NRXN–NLGN–SHANK pathway lead to abnormal synaptogenesis and excess of inhibitory currents. The arrows entering the red
zone illustrate the excess of synaptic/cell growth and inhibitory currents during early brain development.
Current Opinion in Neurobiology 2009, 19:231–234 www.sciencedirect.com
Indeed, knockout mice for Nlgn4 display reduced social
interactions and ultrasonic vocalizations (USV) at the
adult stage [40??]. Mice carrying the R451C mutation
in Nlgn3 display normal  to reduced social interaction
 at the adult stage and a reduction of isolation calls in
pups . However, knockout Nlgn4 and mutant knockin
Nlgn3 display normal to enhanced learning when com-
pared with wild-type mice [32,40??]. The same is true for
the mice carrying a null mutation of Shank1, which
exhibits increased anxiety-related behavior, but show
enhanced spatial learning .
One of the main challenges for basic scientists and
clinicians is to understand how far abnormal cell/synaptic
growth and synaptic function could be reversed. Remark-
ably, in mice with Tsc1/Tsc2 or Pten mutations, the use of
rapamycin, a specific inhibitor of mTORC1, can prevent
and reverse neuronal hypertrophy, resulting in the ame-
lioration of the behavior [43?,44?]. Similarly, abnormal
synaptic functions could be reversed in adult mice model
for fragile X or Rett syndrome [45?,46,47]. The possibility
to reverse the social and USV alterations of the Nlgn3/4
mutant mice has not been tested yet, but the recent
results obtained on mice model for fragile X or Rett
syndrome provide new hopes for the treatment of ASD.
New routes to ASD?
ASD, but most probably many other tracks can lead to this
complex syndrome. Furthermore, even when a pathway is
identified, the diversity of genotype–phenotype relation-
ships observed in patients with ASD indicates that other
modulators such as serotonin and/or melatonin may play
recent results have shed light on the origin of ASD and we
are confident that new pathways will be identified soon to
better understand the many facets of ASD.
This work was supported by the Pasteur Institute, University Denis Diderot
Paris 7, INSERM, CNRS, Assistance Publique-Ho ˆpitaux de Paris, FP6
ENI-NET, FP6 EUSynapse, Fondation Orange, Fondation de France, and
Fondation pour la Recherche Me ´dicale, Fondation FondaMentale.
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