Human Genetics and Cognitive Functions  

  HEADPr. Thomas Bourgeron /
  MEMBERSPr. Thomas Bourgeron, Dr. Fabien Fauchereau, Dr. Hany Goubran-Botros, Marina Konyukh, Claire Leblond, Constance Couwez, Nathalie Lemière

  Annual Report

Our group explores the genetic contribution to human cognitive functions by studying the genetic susceptibility to psychiatric conditions such as autism spectrum disorders (ASD) or obsessive-compulsive disorders (OCD). Using a genetic approach, we have characterized several candidate genes (FAM8A1, KIF13A, GRIK2, NLGNs, PCDHX/Y, ASMT) and identified mutations associated with ASD (NLGN3, NLGN4, NRXN1, SHANK3 and ASMT). Our main results consist in the identification of a synaptic pathway, sensitive to gene dosage, and associated with ASD. Synapses are highly specialized contacts between neurons that constitute the major sites of information processing in the brain. Altered synaptic structure and function are involved in a large number of neurological and psychiatric disorders. Among these diseases, direct or indirect genetic causes involving synaptic proteins have been recently identified. Collectively these diseases have been called "synaptopathies" and their study is an emerging field of neuroscience.

Synapses and autism spectrum disorders

ASD is diagnosed on the basis of three behaviourally altered domains, namely social deficits, impaired language and communication, stereotyped and repetitive behaviour. In the vast majority of the individuals, the origin of the disorder is still unknown. During these last years, our group contributed to a better characterization of the genetic bases of ASD. Several genes are now associated with the condition (Figure), providing a better view of the complex pathways contributing to ASD (anomalies in the number and shape of the synapses, imbalance in excitation/inhibition, increased cell number, high serotonin level).

Four genes were associated with ASD and code for proteins belonging to the same synaptic complex also known as the NRXN-NLGN-SHANK pathway. The first report concerned the X-linked cell adhesion molecules neuroligins NLGN3 and NLGN4X. The third gene identified within this pathway was SHANK3 located on chromosome 22, a region deleted in several individuals with ASD. SHANK3 is a scaffolding protein of the postsynaptic density (PSD), which binds to the NLGN and regulates the structural organization of dendritic spines. SHANK3 seems to be more frequently mutated in cases with ASD/LD and absence of speech than NLGNs. Finally, the collaborative study “The autism genome” identified on chromosome 2pNRXN1as the fourth gene within this pathway mutated in ASD. NRXN1 is a presynaptic partners of the NLGNs.

Atypical synapses in autism spectrum disorders?

Taken together, these results strongly suggest that the NRXN-NLGN-SHANK protein complex has an important function in ASD. Although, there is little data on the specific role of this pathway in the human brain, studies on neuronal cell culture and animal models provided crucial information on its function.

First, neuroligins and neurexins enhance synapse formation in vitro, but, surprisingly, are not required for the generation of synapses in vivo. Indeed, results from knockout (KO) mice demonstrate that neither NLGNs nor neurexins are required for the initial formation of synapses, but both are essential for synaptic function and mouse survival. Therefore, neuroligins may not establish, but may specify and validate synapses via an activity-dependent mechanism, with different neuroligins acting on distinct types of synapses . This model, proposed by Chubykin et al.(2007), reconciles the overexpression and knockout phenotypes and suggests that neuroligins contribute to the activity-dependent formation of neural circuits.

Secondly, neuroligins and neurexins are also emerging as central organizing molecules for excitatory glutamatergic and inhibitory GABAergic synapses in mammalian brain. NLGN1, NLGN3 and NLGN4 are specific to glutamatergic synapses, whereas NLGN2 is restricted to GABAergic synapses. A selectivity for glutamatergic GABAergic synapse is also conferred by alternative splicing of both partners. This role in synaptic specificity is highly relevant to ASD since imbalance between excitation and inhibition could lead to epilepsy, a disease observed in almost 25% of individuals with ASD. Interestingly, the mutant mice carrying the R451C Nlgn3mutation show increased number of GABAergic synapses and inhibitory currents, as well as problems in social interaction. Furthermore, in a recent collaborative study with the group of Nils Brose (Max Planck Institute), we engineered the mutant mice for . These mice present with alteration of social interaction and reduced ultrasonic vocalisation (USV).

Although genetics and functional studies provided very relevant information on the role of the NRXN-NLGN-SHANK complex in the susceptibility to ASD, it was shown that the severity of the syndrome associated with mutations within this pathway could greatly differ from one individual to another (even if they carry identical or similar mutations). This relative heterogeneity in the phenotype indicates that this pathway could be modulated by other genetics and/or environmental factors. Among these factors, we hypothesize that abnormal circadian rhythms may greatly increase the risk, as well as the severity of the disorder.

Circadian rhythms and clock genes in autism spectrum disorders

Despite the fact that sleep is one of the major concernsfor families having a child with ASD, this problem was often considered as an epiphenomenon, and therefore did not catch the attention of the scientific community. However, recent results showing abnormal melatonin synthesis, as well as an efficacy of melatonin therapy for sleep problems observed in ASD, may change this initial disregard from a possible key role of the clock and circadian regulations in ASD.

The most consistent results reporting abnormal circadian rhythms in ASD concern the melatonin synthesis pathway. Melatonin is considered to be the hormonal message for darkness since it is released during the night in all vertebrates examined, independent of whether the animal is diurnally or nocturnally active.It is produced mainly in the pineal gland by the conversion of serotonin to N-acetylserotonin by the rate-limiting enzyme AA-NAT (arylalkylamine N-acetyltransferase), followed by the conversion of N-acetylserotonin (NAS) to melatonin by HIOMT (hydroxyindole O-methyltransferase). At least, five independent groups detected abnormal melatonin levels in ASD. With the exception of Ritvo et al (1993), who reported increased daytime urinary melatonin levels and similar nocturnal values, all the remaining studies found an abnormal decrease of melatonin concentration in individuals with ASD.

In a recent study, we studied the ASMTgene that encodes HIOMT the last enzyme in the melatonin biosynthesis pathway. All ASMTexons and promoters were sequenced in 250 individuals with ASD. Variations affecting the protein sequence of HIOMT (N17K, K81E, G306A and L326F) were enriched in the ASD group, and a splicing mutation (IVS5+2T>C) was present in two families with ASD, but not in controls. In addition, two polymorphisms (rs4446909 and rs5989681) located in the promoter were more frequent in ASD compared to controls (P=0.0006) and were associated with a decrease in ASMTtranscripts in B lymphoblastoid cell lines (P=2x10–10). Biochemical analyses performed on blood platelets of 43 individuals with ASD and 48 controls revealed a highly significant decrease in HIOMT activity (P=2x10-12) and melatonin level (P=3x10–11) in ASD. The HIOMT deficit was also detected in cultured cells of the patients, ruling out inhibitory effects of environmental factors or regulation acting at a higher physiological level.


Based on these results, our project aims now to combine our genetic approach to cell biology and brain imaging, to better characterize, at different integrated levels, the contribution of these genes in the development of language and communication in humans. This knowledge should also shed light on the origin of our ability to communicate, a complex process influenced by genetic/epigenetic factors and the environment.


Figure 1. Left Supposed genetic and neurobiological abnormalities contributing to ASD (from Belmonte and Bourgeron, Nature Neuroscience, 2006). Right. Proteins known or suspected to play a role in the susceptibility to ASD (Persico and Bourgeron, Trends in Neuroscience, 2006).


The Autism Genome Project Consortium. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genetics. 2007 39:319-28.

Durand C, Betancur C, Boeckers TM, Bockmann J, ChasteP, FauchereauF, NygrenG, Rastam M, Gillberg IC, Anckarsäter H, Sponheim E, Goubran-Botros H, Delorme R, Chabane N, Mouren-Simeoni MC,de Mas P, Bieth E, Rogé B, Héron D, Burglen L, Gillberg C, Leboyer M, Bourgeron T. Mutations of the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genetics2006 39:25-7.

Belmonte MK and Bourgeron T. Fragile X Syndrome and Autism at the Intersection of Genetic and Neuronal Networks. Nature Neuroscience(2006) 9:1221-1225.

Persico A. and Bourgeron T. Searching for ways out of the autism maze: Genetic, epigenetic, and environmental clues. Trends in Neurosience(2006) 29, 349-358.

Jamain S, Quach H, Betancur C, Råstam M, Colineaux C, Gillberg IC, Soderstrom H, Giros B, Leboyer M, Gillberg C, Bourgeron T and the Paris study. Mutations of the X-linked neuroligins NLGN3and are associated with autism Nature Genetics(2003) 34, 27-29.

Activity Reports 2007 - Institut Pasteur
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