Disruption of Neurexin 1 Associated with Autism Spectrum Disorder

Kim, Hyung Goo; Kishikawa, Shotaro; Higgins, Anne W.; Seong, Ihn Sik; Donovan, Diana; Shen, Yiping; Lally, Eric; Weiss, Lauren A.; Najm, Juliane; Kutsche, Kerstin; Descartes, Maria; Holt, Lynn; Braddock, Stephen R.; Troxell, Robin; Kaplan, Lee M.; Volkmar, Fred R.; Klin, Ami; Tsatsanis, Katherine; Harris, David J.; Noens, Ilse; Pauls, David L.; Daly, Mark J.; MacDonald, Marcy E.; Morton, Cynthia C.; Quade, Bradley J.; Gusella, James F.

doi:10.1016/j.ajhg.2007.09.011

Cited by 547 publications

(446 citation statements)

References 42 publications

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“…Interestingly, the decrease in the excitatory to inhibitory balance in the neurexin-1␣ KO mice is yet another example of decreased excitatory/inhibitory balance in a genetic mouse model relevant to autism (38,39). We also find that the neurexin-1␣ KO mice display a distinct behavioral phenotype that is consistent in part with cognitive impairments observed in ASDs and schizophrenia, which have been associated with heterozygous deletions of neurexin-1␣ (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). In addition, the moderate extent of the phenotype we observe is in agreement with the viability of neurexin-1␣ KO mice, the fact that other ␣-neurexins are still expressed in neurexin-1␣ KO mice, and the observation that human patients containing a heterozygous deletion of neurexin-1␣ are overall functional (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

Section: Discussionsupporting

confidence: 58%

“…Because KO mice lacking the neurexin-binding partner neuroligin-2 exhibit increased anxiety (37), we examined anxiety-related and locomotor behaviors in neurexin-1␣ KO mice, but detected no significant phenotype (SI Appendix). Some ASD patients with neurexin-1␣ mutations have IQ levels low enough for the patients to be classified as mentally retarted (15). Conversely, a dominant mutation in the postsynaptic neurexin-binding partner neuroligin-3 (R451C) enhances spatial learning in mice (38).…”

Section: Neurexin-1␣ Ko Exhibit Normal Anxiety-like Behaviors Locomotormentioning

confidence: 99%

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Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

Etherton¹,

Blaiss²,

Powell³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

410

369

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Deletions in the neurexin-1␣ gene were identified in large-scale unbiased screens for copy-number variations in patients with autism or schizophrenia. To explore the underlying biology, we studied the electrophysiological and behavioral phenotype of mice lacking neurexin-1␣. Hippocampal slice physiology uncovered a defect in excitatory synaptic strength in neurexin-1␣ deficient mice, as revealed by a decrease in miniature excitatory postsynaptic current (EPSC) frequency and in the input-output relation of evoked postsynaptic potentials. This defect was specific for excitatory synaptic transmission, because no change in inhibitory synaptic transmission was observed in the hippocampus. Behavioral studies revealed that, compared with littermate control mice, neurexin-1␣ deficient mice displayed a decrease in prepulse inhibition, an increase in grooming behaviors, an impairment in nestbuilding activity, and an improvement in motor learning. However, neurexin-1␣ deficient mice did not exhibit any obvious changes in social behaviors or in spatial learning. Together, these data indicate that the neurexin-1␣ deficiency induces a discrete neural phenotype whose extent correlates, at least in part, with impairments observed in human patients.autism ͉ neuroligin ͉ schizophrenia ͉ synaptic cell-adhesion ͉ synapse N eurexins are neuronal cell-surface proteins that were identified as receptors for ␣-latrotoxin, a presynaptic toxin that triggers massive neurotransmitter release (1-3). Neurexins are largely presynaptic proteins that form a transsynaptic celladhesion complex with postsynaptic neuroligins (4, 5). Vertebrates express three neurexin genes, each of which includes two promoters that direct the synthesis of the longer ␣-neurexins and the shorter ␤-neurexins (6, 7). Neurexins are expressed in all neurons, and are subject to extensive alternative splicing, generating Ͼ1,000 splice variants, some of which exhibit highly regulated developmental and spatial expression patterns (8).The properties of neurexins suggested that they function as synaptic recognition molecules (1), and mediate transsynaptic interactions via binding to neuroligins (4). In support of this overall concept, ␣-neurexin triple KO mice exhibit major impairments in synaptic transmission that manifest largely, but not exclusively, as presynaptic changes (9-13). Importantly, ␣-neurexin KO mice do not display a major decrease in the number of excitatory synapses, and only a moderate decrease in inhibitory synapses (9, 13). Thus, neurexins appear to be essential components of synaptic function whose roles extend to several different components of synapses.In recent years, enormous progress in human genetics has led to the identification of multiple genes that are linked to autism spectrum disorders (ASDs) and schizophrenia. Interestingly, copy-number variations in the neurexin-1␣ gene (but not the neurexin-1␤ gene) were repeatedly observed in patients with ASDs (14 -21) and schizophrenia (22-25). Because 0.5% of all ASD cases appear to harbor neurexin-1␣ gen...

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Section: Discussionsupporting

confidence: 58%

Section: Neurexin-1␣ Ko Exhibit Normal Anxiety-like Behaviors Locomotormentioning

confidence: 99%

Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

Etherton¹,

Blaiss²,

Powell³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

410

369

View full text Add to dashboard Cite

show abstract

“…27,31 This patient also had a missense NRXN1 mutation (c.83G4C; p.Gly28Ala). However, although this gene has been associated to ASD, 44 the bioinformatic analysis does not support a pathogenic role for this change.…”

Section: Discussionmentioning

confidence: 89%

Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

et al. 2012

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Autism spectrum disorders (ASDs) include three main conditions: autistic disorder (AD), pervasive developmental disorder, not otherwise specified (PDD-NOS), and Asperger syndrome. It has been shown that many genes associated with ASDs are involved in the neuroligin-neurexin interaction at the glutamate synapse: NLGN3, NLGN4, NRXN1, CNTNAP2, and SHANK3. We screened this last gene in two cohorts of ASD patients (133 patients from US and 88 from Italy). We found 5/221 (2.3%) cases with pathogenic alterations: a 106 kb deletion encompassing the SHANK3 gene, two frameshift mutations leading to premature stop codons, a missense mutation (p.Pro141Ala), and a splicing mutation (c.1820-4 G4A). Additionally, in 17 patients (7.7%) we detected a c.1304 þ 48C4T transition affecting a methylated cytosine in a CpG island. This variant is reported as SNP rs76224556 and was found in both US and Italian controls, but it results significantly more frequent in our cases than in the control cohorts. The variant is also significantly more common among PDD-NOS cases than in AD cases. We also screened this gene in an independent replication cohort of 104 US patients with ASDs, in which we found a missense mutation (p.Ala1468Ser) in 1 patient (0.9%), and in 8 patients (7.7%) we detected the c.1304 þ 48C4T transition. While SHANK3 variants are present in any ASD subtype, the SNP rs76224556 appears to be significantly associated with PDD-NOS cases. This represents the first evidence of a genotype-phenotype correlation in ASDs and highlights the importance of a detailed clinical-neuropsychiatric evaluation for the effective genetic screening of ASD patients.

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“…Multiple groups have established links between different isoforms of NRXN or NLGN and ASD [10,[38][39][40][41][42][43][44][45]. These experiments revealed roles for NRXNs and NLGNs in synapse formation, synapse constitution and the expression of some forms of synaptic plasticity.…”

Section: The Synaptic Theory Of Autismmentioning

confidence: 99%

Shank mutant mice as an animal model of autism

Yoo

Bakes

Bradley

et al. 2014

Phil. Trans. R. Soc. B

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In this review, we focus on the role of the Shank family of proteins in autism. In recent years, autism research has been flourishing. With genetic, molecular, imaging and electrophysiological studies being supported by behavioural studies using animal models, there is real hope that we may soon understand the fundamental pathology of autism. There is also genuine potential to develop a molecular-level pharmacological treatment that may be able to deal with the most severe symptoms of autism, and clinical trials are already underway. The Shank family of proteins has been strongly implicated as a contributing factor in autism in certain individuals and sits at the core of the alleged autistic pathway. Here, we analyse studies that relate Shank to autism and discuss what light this sheds on the possible causes of autism.

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Disruption of Neurexin 1 Associated with Autism Spectrum Disorder

Cited by 547 publications

References 42 publications

Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments

Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

Shank mutant mice as an animal model of autism

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