GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disability
Open accessAbstract
Phenotypic and genetic heterogeneity is predominant in autism spectrum disorders (ASD), for which the molecular and pathophysiological bases are still unclear. Significant comorbidity and genetic overlap between ASD and other neurodevelopmental disorders are also well established. However, little is understood regarding the frequent observation of a wide phenotypic spectrum associated with deleterious mutations affecting a single gene even within multiplex families. We performed a clinical, neurophysiological (in vivo electroencephalography-auditory-evoked related potentials) and genetic (whole-exome sequencing) follow-up analysis of two families with known deleterious NLGN4X gene mutations (either truncating or overexpressing) present in individuals with ASD and/or with intellectual disability (ID). Complete phenotypic evaluation of the pedigrees in the ASD individuals showed common specific autistic behavioural features and neurophysiological patterns (abnormal MisMatch Negativity in response to auditory change) that were absent in healthy parents as well as in family members with isolated ID. Whole-exome sequencing in ASD patients from each family identified a second rare inherited genetic variant, affecting either the GLRB or the ANK3 genes encoding NLGN4X interacting proteins expressed in inhibitory or in excitatory synapses, respectively. The GRLB and ANK3 mutations were absent in relatives with ID as well as in control databases. In summary, our findings provide evidence of a double-hit genetic model focused on excitatory/inhibitory synapses in ASD, that is not found in isolated ID, associated with an atypical in vivo neurophysiological pattern linked to predictive coding.
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Early work on a small group of 5-6-month-old infants who later developed ASD observed faster but less prolonged neural activation and delayed sensitization responses to faces compared with infants who did not develop ASD.
“For example, early work on a small group of 5 -6-month-old infants who later developed ASD observed faster but less prolonged neural activation and delayed sensitization responses to faces compared with infants who did not develop ASD 106”
From Autism spectrum disorder (2020) · cites this paper as [106]
The Results section reports shortened auditory mismatch-response latencies in two ASD patients, not responses to faces in 5–6-month-old infants. Searches for infant face responses and sensitization found no passage addressing the claimed comparison or delayed sensitization. (LLM, conf=0.76)
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CNTN6 Modulates Slit-Robo Signaling in Cortical GABAergic Interneuron Migration
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“Alterations in the E/I equilibrium were first implicated in ASD [26] and have since been reported across a range of NDDs, including ADHD [27-31], ID [11-13], and epilepsy [14-18].”
- Authors
- Bonnet-Brilhault, F., Alirol, S., Blanc, R., Bazaud, S., Marouillat, S., Thépault, R.-A., Andres, C. R., Lemonnier, É., Barthélémy, C., Raynaud, M., Toutain, A., Gomot, M., & Laumonnier, F.
- Affiliations
- Université de Tours (FR)
- Sorbonne Paris Cité (FR)
- Université de Bretagne Occidentale (FR)
- Corresponding author
- Laumonnier, F
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2015-06-09
- Volume
- 21
- Issue
- 3
- Pages
- 411-418
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W1560939387
- Cited by
- 41
- References
- 50
- Citations by year
- 2026: 5 · 2024: 1 · 2023: 5 · 2022: 6 · 2021: 2 · 2020: 6 · 2019: 2 · 2018: 4 · 2017: 7 · 2016: 1 · 2015: 2
- FWCI
- 2.80
- Type
- journal article
- Language
- en
- Open access
- green
- hal.science
- Licence
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- European Commission (241995)
- Institut National de la Santé et de la Recherche Médicale
- Fondation de France
- Université François-Rabelais
- National Heart, Lung, and Blood Institute
- National Institute of Mental Health (RC2MH089929, RC2MH090047, RC2MH089921)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- autism spectrum disorder, intellectual disability, ANK3, GABAergic synapses, glutamatergic synapses, mismatch negativity, predictive coding, neurodevelopmental disorders, phenotypic heterogeneity
- MeSH terms
- Acoustic Stimulation, Autistic Disorder, Child, Preschool, Electroencephalography, Evoked Potentials, Auditory, Family Health, Female, Follow-Up Studies, gamma-Aminobutyric Acid, Humans, Male, Intellectual Disability, Severity of Illness Index, Signal Transduction, Cell Adhesion Molecules, Neuronal, Glutamic Acid, Genetic Predisposition to Disease, Genomics
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