Mutation of Semaphorin-6A disrupts limbic and cortical connectivity and models neurodevelopmental psychopathology.
Authors
Rünker, Annette EO'Tuathaigh, Colm
Dunleavy, Mark
Morris, Derek W
Little, Graham E
Corvin, Aiden P
Gill, Michael
Henshall, David C
Waddington, John L
Mitchell, Kevin J
Affiliation
Smurfit Institute of Genetics and Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.Issue Date
2011MeSH
AnimalsAnxiety
Behavior, Animal
Disease Models, Animal
Female
Gait
Humans
Limbic System
Locomotion
Male
Memory
Mental Disorders
Mice
Mice, Inbred C57BL
Mice, Neurologic Mutants
Mutation
Nerve Net
Phenotype
Prefrontal Cortex
Semaphorins
Metadata
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Mutation of Semaphorin-6A disrupts limbic and cortical connectivity and models neurodevelopmental psychopathology. 2011, 6 (11):e26488 PLoS ONEJournal
PloS oneDOI
10.1371/journal.pone.0026488PubMed ID
22132072Abstract
Psychiatric disorders such as schizophrenia and autism are characterised by cellular disorganisation and dysconnectivity across the brain and can be caused by mutations in genes that control neurodevelopmental processes. To examine how neurodevelopmental defects can affect brain function and behaviour, we have comprehensively investigated the consequences of mutation of one such gene, Semaphorin-6A, on cellular organisation, axonal projection patterns, behaviour and physiology in mice. These analyses reveal a spectrum of widespread but subtle anatomical defects in Sema6A mutants, notably in limbic and cortical cellular organisation, lamination and connectivity. These mutants display concomitant alterations in the electroencephalogram and hyper-exploratory behaviour, which are characteristic of models of psychosis and reversible by the antipsychotic clozapine. They also show altered social interaction and deficits in object recognition and working memory. Mice with mutations in Sema6A or the interacting genes may thus represent a highly informative model for how neurodevelopmental defects can lead to anatomical dysconnectivity, resulting, either directly or through reactive mechanisms, in dysfunction at the level of neuronal networks with associated behavioural phenotypes of relevance to psychiatric disorders. The biological data presented here also make these genes plausible candidates to explain human linkage findings for schizophrenia and autism.Item Type
ArticleLanguage
enISSN
1932-6203ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0026488
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