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Experience-dependent plasticity modulating cognitive deficits in schizophrenia

We have demonstrated that onset and progression of Huntington’s disease, an autosomal dominant disorder previously considered the epitome of genetic determinism, as well as other brain disorders, can be beneficially modulated by environmental stimulation. Environmental factors also modulate cortical development and several pathways that are key to the genesis of psychiatric symptoms.

Aims

This project aims to investigate mechanisms mediating gene-environment interactions and experience-dependent plasticity in the cerebral cortex, continuing our work on a signaling pathway, which has recently been implicated in the pathogenesis of schizophrenia.

Cognitive dysfunction appears as a core feature of psychiatric disorders such as schizophrenia. There is a need for better understanding of cognitive impairments in rodent models of psychiatric disorders in order to elucidate the pathogenic mechanisms and to develop more effective therapies.  

We propose that an intra-neuronal signaling pathway, which includes specific glutamate receptors, as well as brain-derived neurotrophic factor (BDNF), is required for experience-dependent maturation and plasticity of inter-neuronal circuitry in the neocortex and hippocampus.

We will carry out behavioural, cellular and molecular analysis of wild-type and gene-edited mice, following specific environmental manipulations, to establish the effect of environmental modulators on these molecular mediators in cortical plasticity and associated aspects of behaviour and cognition.

Key References:

Hannan AJ, Blakemore C, Katsnelson A, Vitalis T, Huber KM, Bear M, Roder J, Kim D, et al. PLC-beta1, activated via mGluRs, mediates activity-dependent differentiation in cerebral cortex. Nature Neurosci. 2001;4:282-8.

Spires TL, Molnár Z, Kind PC, Cordery PM, Upton AL, Blakemore C, Hannan AJ. Activity-dependent regulation of synapse and dendritic spine morphology in developing barrel cortex requires phospholipase C-beta1 signalling. Cereb. Cortex 2005;15:385-93.

Nithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nature Rev. Neurosci. 2006;7:697-709.

McOmish CE, Hannan AJ. Enviromimetics: exploring gene-environment interactions to identify therapeutic targets for brain disorders. Expert Opin. Ther. Targets 2007;11:899-913.

McOmish CE, Burrows E, Howard M, Scarr E, Kim D, Shin HS, Dean B, van den Buuse M, Hannan AJ. Phospholipase C-beta1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration. Mol. Psychiatry 2008;13:661-72.

McOmish CE, Burrows EL, Hannan AJ. Identifying novel interventional strategies for psychiatric disorders: integrating genomics, 'enviromics' and gene-environment interactions in valid preclinical models. Br. J. Pharmacol. 2014;171:4719-28.

Burrows EL, McOmish CE, Buret LS, Van den Buuse M, Hannan AJ. Environmental enrichment ameliorates behavioral impairments modeling schizophrenia in mice lacking metabotropic glutamate receptor 5. Neuropsychopharmacology 2015;40:1947-56.

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