A synaptic trek to autism.
ABSTRACT 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 retardation, typical autism, or Asperger syndrome. The mTOR/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.
- SourceAvailable from: Winrich A Freiwald[Show abstract] [Hide abstract]
ABSTRACT: Facial interactions are prominent behaviors in primates. Primate facial signaling, which includes the expression of emotions, mimicking of facial movements, and gaze interactions, is visually dominated. Correspondingly, in primate brains an elaborate network of face processing areas exists within visual cortex. But other mammals also communicate through facial interactions using additional sensory modalities. In rodents, multisensory facial interactions are involved in aggressive behaviors and social transmission of food preferences. The eusocial naked mole-rat, whose face is dominated by prominent incisors, uses facial aggression to enforce reproductive suppression. In burrow-living mammals like the naked mole-rat in particular, and in rodents in general, somatosensory face representations in cortex are enlarged. Diversity of sensory domains mediating facial communication might belie underlying common mechanisms. As a case in point, neurogenetics has revealed strongly heritable traits in face processing and identified gene defects that disrupt facial interactions both in humans and rodents.Current opinion in neurobiology 12/2011; 22(2):259-66. · 7.21 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Abnormal immune responses have been reported to be associated with autism. A number of studies showed that cytokines were increased in the blood, brain, and cerebrospinal fluid of autistic subjects. Elevated IL-6 in autistic brain has been a consistent finding. However, the mechanisms by which IL-6 may be involved in the pathogenesis of autism are not well understood. Here we show that mice with elevated IL-6 in the brain display many autistic features, including impaired cognitive abilities, deficits in learning, abnormal anxiety traits and habituations, as well as decreased social interactions. IL-6 elevation caused alterations in excitatory and inhibitory synaptic formations and disrupted the balance of excitatory/inhibitory synaptic transmissions. IL-6 elevation also resulted in an abnormal change in the shape, length and distributing pattern of dendritic spines. These findings suggest that IL-6 elevation in the brain could mediate autistic-like behaviors, possibly through the imbalances of neural circuitry and impairments of synaptic plasticity.Biochimica et Biophysica Acta 02/2012; 1822(6):831-42. · 4.66 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) are widespread environmental contaminants linked to neuropsychological dysfunction in children. NDL PCBs increase spontaneous Ca(2+) oscillations in neurons by stabilizing ryanodine receptor (RyR) calcium release channels in the open configuration, which results in CREB-dependent dendritic outgrowth. In this study, we address the question of whether activation of CREB by NDL PCBs also triggers dendritic spine formation. Nanomolar concentrations of PCB 95, a NDL congener with potent RyR activity, significantly increased spine density and the frequency of miniature EPSCs in primary dissociated rat hippocampal cultures coincident with upregulation of miR132. Inhibition of RyR, CREB, or miR132 as well as expression of a mutant p250GAP cDNA construct that is not suppressed by miR132 blocked PCB 95 effects on spines and miniature EPSCs. PCB 95 also induced spine formation via RyR- and miR132-dependent mechanisms in hippocampal slice cultures. These data demonstrate a novel mechanism of PCB developmental neurotoxicity whereby RyR sensitization modulates spine formation and synaptogenesis via CREB-mediated miR132 upregulation, which in turn suppresses the translation of p250GAP, a negative regulator of synaptogenesis. In light of recent evidence implicating miR132 dysregulation in Rett syndrome and schizophrenia, these findings identify NDL PCBs as potential environmental risk factors for neurodevelopmental disorders.Journal of Neuroscience 01/2014; 34(3):717-25. · 6.91 Impact Factor
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 (firstname.lastname@example.org)
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, 19:231–234www.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.
References and recommended reading
Papers of particular interest published within the period of review have
been highlighted as:
? of special interest
?? of outstanding interest
1. Huttenlocher PR, Dabholkar AS: Regional differences in
synaptogenesisin humancerebral cortex.J CompNeurol1997,
2.Lainhart JE, Bigler ED, Bocian M, Coon H, Dinh E, Dawson G,
Deutsch CK, Dunn M, Estes A, Tager-Flusberg H et al.: Head
circumference and height in autism: a study by the
Collaborative Program of Excellence in Autism. Am J Med
Genet A 2006, 140:2257-2274.
3. Sacco R, Militerni R, Frolli A, Bravaccio C, Gritti A, Elia M,
Curatolo P, Manzi B, Trillo S, Lenti C et al.: Clinical,
morphological, and biochemical correlates of head
circumference in autism. Biol Psychiatry 2007, 62:1038-1047.
4.Amaral DG, Schumann CM, Nordahl CW: Neuroanatomy of
autism. Trends Neurosci 2008, 31:137-145.
5.Courchesne E, Carper R, Akshoomoff N: Evidence of brain
overgrowth in the first year of life in autism. JAMA 2003,
6.Dementieva YA, Vance DD, Donnelly SL, Elston LA, Wolpert CM,
Ravan SA, DeLong GR, Abramson RK, Wright HH, Cuccaro ML:
Accelerated head growth in early development of individuals
with autism. Pediatr Neurol 2005, 32:102-108.
7.Williams CA, Dagli A, Battaglia A: Genetic disorders associated
with macrocephaly. Am J Med Genet A 2008, 146A:2023-2037.
Tavazoie SF, Alvarez VA, Ridenour DA, Kwiatkowski DJ,
Sabatini BL: Regulation of neuronal morphology and function
by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci 2005,
The first demonstration of the direct link between mutations in Tsc1 and
Tsc2 and neuronal morphology and function.
9.Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W,
Li Y, Baker SJ, Parada LF: Pten regulates neuronal arborization
and social interaction in mice. Neuron 2006, 50:377-388.
10. Kelleher RJ 3rd, Bear MF: The autistic neuron: troubled
translation? Cell 2008, 135:401-406.
11. Page DT, Kuti OJ, Prestia C, Sur M: Haploinsufficiency for Pten
and Serotonin transporter cooperatively influences brain
size and social behavior. Proc Natl Acad Sci U S A 2009,
12. Zoghbi HY: Postnatal neurodevelopmental disorders: meeting
at the synapse? Science 2003, 302:826-830.
13. Belmonte MK, Bourgeron T: Fragile X syndrome and autism at
the intersection of genetic and neural networks. Nat Neurosci
14. Canitano R: Epilepsy in autism spectrum disorders. Eur Child
Adolesc Psychiatry 2007, 16:61-66.
Jamain S, Quach H, Betancur C, Rastam M, Colineaux C,
Gillberg IC, Soderstrom H, Giros B, Leboyer M, Gillberg C et al.:
Mutations of the X-linked genes encoding neuroligins NLGN3
and NLGN4 are associated with autism. Nat Genet 2003,
The first report of mutations in the synaptic cell adhesion molecules
NLGN3/4 in typical autism and Asperger syndrome.
16. Laumonnier F, Bonnet-Brilhault F, Gomot M, Blanc R, David A,
Moizard MP, Raynaud M, Ronce N, Lemonnier E, Calvas P et al.:
X-linked mental retardation and autism are associated with a
mutation in the NLGN4 gene, a member of the neuroligin
family. Am J Hum Genet 2004, 74:552-557.
17. Chih B, Afridi SK, Clark L, Scheiffele P: Disorder-associated
mutations lead to functional inactivation of neuroligins. Hum
Mol Genet 2004, 13:1471-1477.
18. Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P,
Fauchereau F, Nygren G, Rastam M, Gillberg IC, Anckarsater H
et al.: Mutations in the gene encoding the synaptic scaffolding
protein SHANK3 are associated with autism spectrum
disorders. Nat Genet 2007, 39:25-27.
19. Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J,
Liu XQ, Vincent JB, Skaug JL, Thompson AP, Senman L et al.:
Mapping autism risk loci using genetic linkage and
chromosomal rearrangements. Nat Genet 2007, 39:319-328.
20. KimHG,Kishikawa S,Higgins AW, SeongIS, Donovan DJ,ShenY,
Lally E,Weiss LA,Najm J, Kutsche K et al.:Disruptionofneurexin
1 associated with autism spectrum disorder. Am J Hum Genet
21. Bakkaloglu B, O’Roak BJ, Louvi A, Gupta AR, Abelson JF,
Morgan TM,ChawarskaK,Klin A, Ercan-Sencicek AG, Stillman AA
et al.: Molecular cytogenetic analysis and resequencing of
contactin associated protein-like 2 in autism spectrum
disorders. Am J Hum Genet 2008, 82:165-173.
A synaptic trek to autism Bourgeron233
Current Opinion in Neurobiology 2009, 19:231–234
22. Alarcon M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV,
Bomar JM, Sebat J, Wigler M, Martin CL, Ledbetter DH et al.:
Linkage, association, and gene-expression analyses identify
CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet
23. Arking DE, Cutler DJ, Brune CW, Teslovich TM, West K, Ikeda M,
Rea A,Guy M,Lin S, CookEHetal.:A common genetic variant in
the neurexin superfamily member CNTNAP2 increases familial
risk of autism. Am J Hum Genet 2008, 82:160-164.
24. Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J,
Shago M, Moessner R, Pinto D, Ren Y et al.: Structural variation
of chromosomes in autism spectrum disorder. Am J Hum
Genet 2008, 82:477-488.
25. Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS,
Mukaddes NM, Balkhy S, Gascon G, Hashmi A et al.: Identifying
autism loci and genes by tracing recent shared ancestry.
Science 2008, 321:218-223.
26. Roussignol G, Ango F, Romorini S, Tu JC, Sala C, Worley PF,
Bockaert J, Fagni L: Shank expression is sufficient to induce
functional dendritic spine synapses in aspiny neurons.
J Neurosci 2005, 25:3560-3570.
Using an elegant in vitro system, the authors reveal the crucial role of the
Neuroligins in synapse formation.
Scheiffele P, Fan J, Choih J, Fetter R, Serafini T: Neuroligin
expressed in nonneuronal cells triggers presynaptic
development in contacting axons. Cell 2000, 101:657-669.
Varoqueaux F, Aramuni G, Rawson RL, Mohrmann R, Missler M,
Gottmann K, Zhang W, Sudhof TC, Brose N: Neuroligins
determine synapse maturation and function. Neuron 2006,
See annotation to Ref. [29?].
Chubykin AA, Atasoy D, Etherton MR, Brose N, Kavalali ET,
Gibson JR, Sudhof TC: Activity-dependent validation of
excitatory versus inhibitory synapses by neuroligin-1 versus
neuroligin-2. Neuron 2007, 54:919-931.
Along withRef.[28??]thisstudyrevealsfor thefirst timetheimpact ofNlgn
mutations in mice. In vivo, the Nlgn mutations affect synapse maturation
and activity-dependent validation of the synapses.
30. Graf ER, Zhang X, Jin SX, Linhoff MW, Craig AM: Neurexins
induce differentiation of GABA and glutamate postsynaptic
specializations via neuroligins. Cell 2004, 119:1013-1026.
between excitatory and inhibitory synapses is controlled by
PSD-95 and neuroligin. Proc Natl Acad Sci U S A 2004,
32. Tabuchi K,BlundellJ,EthertonMR,HammerRE,LiuX,Powell CM,
Sudhof TC: A neuroligin-3 mutation implicated in autism
increases inhibitory synaptic transmission in mice. Science
33. Dani VS, Chang Q, Maffei A, Turrigiano GG, Jaenisch R,
Nelson SB: Reduced cortical activity due to a shift in the
balance between excitation and inhibition in a mouse model of
34. Sadakata T, Washida M, Iwayama Y, Shoji S, Sato Y, Ohkura T,
Katoh-Semba R, Nakajima M, Sekine Y, Tanaka M et al.: Autistic-
like phenotypes in Cadps2-knockout mice and aberrant
CADPS2 splicing in autistic patients. J Clin Invest 2007,
35. Rinaldi T, Silberberg G, Markram H: Hyperconnectivity of local
neocortical microcircuitry induced by prenatal exposure to
valproic acid. Cereb Cortex 2008, 18:763-770.
36. Mataga N, Mizuguchi Y, Hensch TK: Experience-dependent
pruning of dendritic spines in visual cortex by tissue
plasminogen activator. Neuron 2004, 44:1031-1041.
37. Hensch TK: Critical period plasticity in local cortical circuits.
Nat Rev Neurosci 2005, 6:877-888.
38. Gibson JR, Bartley AF, Hays SA, Huber KM: Imbalance of
neocortical excitation and inhibition and altered UP states
reflect network hyperexcitability in the mouse model of fragile
X syndrome. J Neurophysiol 2008, 100:2615-2626.
39. Uhlhaas PJ, Singer W: What do disturbances in neural
synchrony tell us about autism? Biol Psychiatry 2007,
Jamain S, Radyushkin K, Hammerschmidt K, Granon S,
Boretius S, Varoqueaux F, Ramanantsoa N, Gallego J,
Ronnenberg A, Winter D et al.: Reduced social interaction and
ultrasonic communication in a mouse model of monogenic
heritable autism. Proc Natl Acad Sci U S A 2008, 105:1710-1715.
The first report of an alteration of ultrasonic vocalizations in a mice model
of autism spectrum disorder.
41. Chadman KK, Gong S, Scattoni ML, Boltuck SE, Gandhy SU,
Heintz N, Crawley JN: Minimal aberrant behavioural
phenotypes of Neuroligin-3 R451C knockin mice. Autism Res
42. Hung AY, Futai K, Sala C, Valtschanoff JG, Ryu J, Woodworth MA,
Kidd FL, Sung CC, Miyakawa T, Bear MF et al.: Smaller dendritic
spines, weaker synaptic transmission, but enhanced
spatial learning in mice lacking Shank1. J Neurosci 2008,
See annotation to Ref. [45?].
Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowski DJ,
Ramesh V, Silva AJ: Reversal of learning deficits in a Tsc2+/S
mouse model of tuberous sclerosis. Nat Med 2008, 14:843-848.
Zhou J, Blundell J, Ogawa S, Kwon CH, Zhang W, Sinton C,
Powell CM, Parada LF: Pharmacological inhibition of mTORC1
suppresses anatomical, cellular, and behavioral abnormalities
in neural-specific Pten knock-out mice. J Neurosci 2009,
See annotation to Ref. [45?].
Along with Refs. [43?,44?] this study reports that anatomical, neurological,
and behavioral defects can be reversed in animal models of autism.
Guy J, Gan J, Selfridge J, Cobb S, Bird A: Reversal of
neurological defects in a mouse model of Rett syndrome.
Science 2007, 315:1143-1147.
46. de Vrij FM, Levenga J, van der Linde HC, Koekkoek SK, De
Zeeuw CI, Nelson DL, Oostra BA, Willemsen R: Rescue of
behavioral phenotype and neuronal protrusion morphology in
Fmr1 KO mice. Neurobiol Dis 2008, 31:127-132.
Bear MF: Correction of fragile X syndrome in mice. Neuron
48. Bourgeron T: The possible interplay of synaptic and clock
genes in autism spectrum disorders. Cold Spring Harb Symp
Quant Biol 2007, 72:645-654.
Melke J, Goubran Botros H, Chaste P, Betancur C, Nygren G,
Anckarsater H, Rastam M, Stahlberg O, Gillberg IC, Delorme R
et al.: Abnormal melatonin synthesis in autism spectrum
disorders. Mol Psychiatry 2008, 13:90-98.
The first report of a primary deficit of melatonin synthesis in patients with
ASD. This deficit could directly increase the risk of abnormal synaptic
homeostasis in ASD or indirectly by altering the sleep–wake cycles.
Current Opinion in Neurobiology 2009, 19:231–234www.sciencedirect.com