Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility

Ó'Dúshláine, Colm; Kenny, Elaine; Heron, Elizabeth A.; Donohoe, Gary; Gill, Michael; Morris, Derek W.; Corvin, Aiden

doi:10.1038/mp.2010.7

Cited by 196 publications

(172 citation statements)

References 40 publications

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“…4). In addition, mutations in CNTNAP2 also have been linked to epilepsy (5-7), Tourette syndrome (8,9), schizophrenia (5,7,10), attention deficit hyperactivity disorder (ADHD) (11), learning disability (12,13), and language impairment (14)(15)(16). Thus, CNTNAP2 is of central importance for human brain function, as additionally shown by recent in vivo MRI studies in which variations in the CNTNAP2 gene were associated with reduced frontal gray matter and altered functional connectivity (17,18).…”

mentioning

confidence: 71%

Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development

Anderson

Galfin

et al. 2012

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

211

192

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Mutations in the contactin-associated protein 2 (CNTNAP2) gene encoding CASPR2, a neurexin-related cell-adhesion molecule, predispose to autism, but the function of CASPR2 in neural circuit assembly remains largely unknown. In a knockdown survey of autism candidate genes, we found that CASPR2 is required for normal development of neural networks. RNAi-mediated knockdown of CASPR2 produced a cell-autonomous decrease in dendritic arborization and spine development in pyramidal neurons, leading to a global decline in excitatory and inhibitory synapse numbers and a decrease in synaptic transmission without a detectable change in the properties of these synapses. Our data suggest that in addition to the previously described role of CASPR2 in mature neurons, where CASPR2 organizes nodal microdomains of myelinated axons, CASPR2 performs an earlier organizational function in developing neurons that is essential for neural circuit assembly and operates coincident with the time of autism spectrum disorder (ASD) pathogenesis.dendrite | synaptogenesis A utism spectrum disorders (ASDs) comprise a heterogeneous group of early developmental diseases characterized by repetitive and stereotypic behaviors and impairments in social interactions and language development. ASDs are highly heritable, with recent studies linking mutations at hundreds of genes to ASDs (1-3). These findings raised the fundamental question of how these genes might act in neural circuits without being essential for all brain function. Here, we have attempted to address this question by using a Ca 2+ -imaging screening platform to visualize changes in excitatory network activity following shRNA-mediated knockdown (KD) of prominent cell-adhesion molecules that have been repeatedly implicated in the development of ASDs. We found that molecular manipulation of several ASD candidate genes profoundly influences network activity as monitored by this assay. We observed the biggest effects with the neuronal cell-adhesion molecule contactin-associated protein 2 (CASPR2) that is encoded by the CNTNAP2 gene, leading us to specifically focus on the mechanisms by which this cell-adhesion molecule influences neural circuit development.Mutations in the CNTNAP2 gene have been repeatedly identified in ASD patients (for review, see ref. 4). In addition, mutations in CNTNAP2 also have been linked to epilepsy (5-7), Tourette syndrome (8, 9), schizophrenia (5, 7, 10), attention deficit hyperactivity disorder (ADHD) (11), learning disability (12, 13), and language impairment (14-16). Thus, CNTNAP2 is of central importance for human brain function, as additionally shown by recent in vivo MRI studies in which variations in the CNTNAP2 gene were associated with reduced frontal gray matter and altered functional connectivity (17,18).CASPR2 is a member of the contactin-associated protein family (19). CASPRs are referred to as neurexin IV in Drosophila and are highly homologous to neurexins, which are presynaptic celladhesion molecules (20-23). CASPR2 is best known for its role in mye...

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confidence: 71%

Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development

Anderson

Galfin

et al. 2012

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

211

192

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“…Subjects with autism have been shown to carry copy number variations, complex rearrangements, an intron deletion, a promoter deletion, and amino acid substitutions (12)(13)(14)(15)(16)(17)(18)(19)(20). Disruptions detected in schizophrenia include deletion of exons 9-24, an intron deletion, and copy number variations (21)(22)(23)(24)(25). Other disease-associated disruptions include a large deletion, intron deletion in attention deficit and hyperactivity disorder (26,27), deletion of exons 2-4 in epilepsy (28,29), and deletion of exons 2-4 in speech delay (30).…”

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confidence: 99%

Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein-like 2 /Caspr2 knockout neurons

Varea¹,

Martín-de-Saavedra²,

Kopeikina³

et al. 2015

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

120

114

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Central glutamatergic synapses and the molecular pathways that control them are emerging as common substrates in the pathogenesis of mental disorders. Genetic variation in the contactin associated protein-like 2 (CNTNAP2) gene, including copy number variations, exon deletions, truncations, single nucleotide variants, and polymorphisms have been associated with intellectual disability, epilepsy, schizophrenia, language disorders, and autism. CNTNAP2, encoded by Cntnap2, is required for dendritic spine development and its absence causes disease-related phenotypes in mice. However, the mechanisms whereby CNTNAP2 regulates glutamatergic synapses are not known, and cellular phenotypes have not been investigated in Cntnap2 knockout neurons. Here we show that CNTNAP2 is present in dendritic spines, as well as axons and soma. Structured illumination superresolution microscopy reveals closer proximity to excitatory, rather than inhibitory synaptic markers. CNTNAP2 does not promote the formation of synapses and cultured neurons from Cntnap2 knockout mice do not show early defects in axon and dendrite outgrowth, suggesting that CNTNAP2 is not required at this stage. However, mature neurons from knockout mice show reduced spine density and levels of GluA1 subunits of AMPA receptors in spines. Unexpectedly, knockout neurons show large cytoplasmic aggregates of GluA1. Here we characterize, for the first time to our knowledge, synaptic phenotypes in Cntnap2 knockout neurons and reveal a novel role for CNTNAP2 in GluA1 trafficking. Taken together, our findings provide insight into the biological roles of CNTNAP2 and into the pathogenesis of CNTNAP2-associated neuropsychiatric disorders.A bnormalities in excitatory synapses of cortical pyramidal neurons have emerged as key cellular substrates in the pathogenesis of several psychiatric disorders. Disease-specific disruptions in synaptic morphology or number and glutamate receptors accompany several neuropsychiatric disorders, particularly those that involve deficits in information processing (1). In support of this view, postmortem neuropathological studies found altered dendritic spine density on cortical pyramidal neurons in individuals with intellectual disability (2), autism spectrum disorders (3), and schizophrenia (4). Dendritic spines are the sites of the majority of excitatory glutamatergic synapses in the mammalian brain and represent the postsynaptic compartment of these synapses. Spines are rich in actin, and their morphology changes during development and in various physiological conditions (5). Spines contain glutamate receptors, of which the AMPA subtype are the ones responsible for fast neurotransmission (6). AMPA receptors, like other membrane proteins, are processed in the endoplasmic reticulum and the Golgi complex, then delivered to synapses by forward trafficking mechanisms (7). At the synapse, they undergo constitutive and regulated exo-and endocytosis, known to modulate synapse strength (6). Together, changes in spine number and morphology, along with glutam...

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“…Recently, a PBA analysis, which combined GSEA and Fisher exact test, for 1 single SZ GWAS (GAIN_EA) has found that the metabolism of glutamate, the process of apoptosis, inflammation, and immune system could be associated with SZ [35]. The other PBA analysis of SZ, which utilized SNP ratio test, for 2 SZ GWASs, namely GAIN_EA and ISC (International Schizophrenia Consortium), identified that pathway 'cell adhesion molecule (CAM)' (an immune-related pathway) is associated with SZ [27]. This research has also found that CAM is also associated with BD (by analyzing WTCCC BD GWAS [30]).…”

Section: Discussionmentioning

confidence: 99%

Pathway-based analysis for genome-wide association studies of schizophrenia to provide new insight in schizophrenia study

Zhang

et al. 2011

Chin. Sci. Bull.

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Schizophrenia (SZ) is an inheritable complex mental disease. There have been several genome-wide association studies (GWASs) of SZ to identify novel genetic susceptibility factors. To further interpret SZ GWASs, pathway-based analysis (PBA), which considers the combined effect of variants and identifies pathways associated with traits, provides a feasible solution to discover the biological function and mechanism of SZ. Furthermore, to investigate the common pathways between SZ and bipolar disorder (BD) will help explore common mechanism between psychiatric phenotypes. We performed a PBA, called improved gene set enrichment analysis (i-GSEA), on 3 independent GWASs of SZ to identify pathways associated with SZ. The results were further compared to the BD-associated pathways identified by i-GSEA for 2 BD GWASs and from literature reports. Our analysis identified a highly statistically significant association between SZ and pathway 'substrate specific channel activity' in all 3 SZ GWASs (false discovery rate (FDR) < 0.05). This association has not been reported elsewhere before. This pathway was also identified by PBA for 2 independent BD GWASs. Our results suggest that pathway 'substrate specific channel activity' is statistically significantly associated with SZ, and SZ and BD share the common biological function and mechanism represented by this pathway.

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Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility

Cited by 196 publications

References 40 publications

Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development

Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development

Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein-like 2 /Caspr2 knockout neurons

Pathway-based analysis for genome-wide association studies of schizophrenia to provide new insight in schizophrenia study

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