Mutation of Semaphorin-6A Disrupts Limbic and Cortical Connectivity and Models Neurodevelopmental Psychopathology

Abstract

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.

In This Issue/Abstract Thinking: Of Mice, Monkeys, and Men

“…A recent study of the semaphorin-6A gene mutation related disruptions in limbic and cortical cellular organization, lamination and connectivity to concomitant alterations on the electroencephalogram, and hyperexploratory behavior that is characteristic of models of psychosis and reversible by the antipsychotic clozapine. 3 Myshkin mice carrying an inactivating mutation in the neuron-specific Na ϩ ,K ϩ -adenosine triphosphatase ␣3 subunit exhibit a behavioral profile similar to patients with bipolar disorder in the manic state. 4 Aside from being ameliorated by lithium and valproic acid, this mania-like phenotype was rescued by the transgenic expression of a functional Na ϩ ,K ϩ -adenosine triphosphatase ␣3 protein, which may be an important target for new antimanic therapies.…”

Exploration of known stereotypic behaviour-related candidate genes in equine crib-biting

“…The semaphorin gene (SEMA6) was studied here because it has been implicated in behavioural disturbances in humans (Mann et al, 2007). Sema6A-deficient mice revealed a hyperactive phenotype, and although it was not accompanied by an increase in stereotypic behaviours, it was reflected in both increased locomotion and increased exploration (Rünker et al, 2010). In laboratory mice (Würbel and Stauffacher, 1996) and bank voles (Cooper et al, 1996), differences in the level of stereotypic performance appear to be related to increased general activity.…”

“…Association with the CDH2 region was found in a canine compulsive disorder (Dodman et al, 2010). Semaphorin genes have been implicated in psychiatric disorders in humans (Mann et al, 2007) and Sema6A-deficient mice revealed a hyperactive phenotype (Rünker et al, 2010). Differences in the level of stereotypic performance appear to be related to increased general activity in laboratory mice (Würbel and Stauffacher, 1996), bank voles (Cooper et al, 1996) and horses (Vecchiotti and Galanti, 1986).…”

Towards an understanding of semaphorin signalling in the spinal cord

“…Notwithstanding, clear evidence showing semaphorin involvement in guiding sensory and motor growth cones in the spinal cord has not been forthcoming. Sema6A has attracted attention due to its involvement in corticospinal tract formation (Runker et al, 2011). It is expressed in oligodendrocyte precursors during brain development, where it plays roles in their differentiation and myelinating functions (Bernard et al, 2012;Shim et al, 2012).…”

“…Altered semaphorin function has been linked with an array of neurological disorders including seizures (Sahay et al, 2005), Alzheimer's disease (Good et al, 2004), autism (Runker et al, 2011), Parkinson's disease (Maraganore et al, 2005), motor neuron disease (Winter et al, 2006) and spinal cord injury (SCI), where their effects are mediated by their involvement at the glial scar (Bolsover et al, 2008;Kopp et al, 2010). Multiple factors contribute to the failure of axonal regeneration following SCI, including neuronal death, loss of growth factors, loss of myelin, disrupted vasculature and growth inhibitory signals stemming from the glial scar, such as chondroitin sulphate proteoglycan (CSPG), MAG, nogo and semaphorins (Silver and Miller, 2004).…”