Quick Project Snapshot

Experience-dependent plasticity modulating cognitive deficits in schizophrenia

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.

Most major brain disorders, including schizophrenia, are a product of complex interactions between genes and environmental factors. 

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.

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.

 

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.

Epigenetics and Neural Plasticity Laboratory

The Neural Plasticity Laboratory investigates gene-environment interactions and experience-dependent plasticity in the healthy and diseased brain, using a variety of experimental approaches.  This includes research using a model of Huntington’s disease (HD), a tandem repeat disorder, where we are following up our discoveries regarding the beneficial effects of environmental enrichment (enhanced cognitive stimulation and physical activity) and exercise, as well as depression and dementia-like symptoms associated with abnormalities of brain plasticity.  Furthermore, we recently discovered that chronic stress can accelerate onset of HD, and are investigating these neurotoxic effects of stress in HD and other brain disorders.

Many neurological and psychiatric disorders have their origins in abnormal maturation of the brain, including the billions of neurons exquisitely connected by trillions of synapses. We are also investigating how genetic and environmental factors combine to cause specific disorders of brain development and cognition, including schizophrenia and autism spectrum disorders (ASD).  We are interested in the mechanisms whereby specific genes regulate maturation of the brain and are dynamically regulated by interaction with the environment in conditions like ASD and schizophrenia. 

Our research links data at behavioural and cognitive levels to underlying cellular and molecular mechanisms.  We use a variety of behavioural tools, including automated touchscreen testing of cognition and high-throughput data analysis of vocalization and communication, that are directly translatable to clinical tests.  We are establishing the extent to which experience-dependent plasticity, including adult neurogenesis and synaptic plasticity, can modulate these behavioural and cognitive endophenotypes, in models with targeted genome editing.  This cellular level of understanding is linked, in turn, to molecular mechanisms, including epigenetics, transcriptomics and proteomics.

Based on this research, and the identification of key target molecules, we are also exploring the concept of ‘enviromimetics’, therapeutics that mimic or enhance the beneficial effects of cognitive stimulation and physical exercise.  One goal is to develop such therapeutic agents to help reduce the personal and societal burdens of devastating brain disorders such as schizophrenia, HD and dementia.

All Projects by this Lab

Investigation of paternal influence on offspring mental healthUtilising Touchscreen technology for preclinical modeling of attention in autism spectrum disorderInvestigating social communication in the Neuroligin 3 mouse model of AutismInvestigating the inherited paternal influence on offspring cognition and behaviourExperience-dependent plasticity modulating cognitive deficits in schizophreniaGene-environment interactions modulating dementia and depression in a tandem repeat disorder

Behavioural Neuroscience

The Division of Behavioural Neuroscience focuses on the use and development of models that reflect aspects of human disorders such as addiction, anxiety, depression, schizophrenia, autism and neurodegenerative conditions such as Huntington’s disease. The Cognitive Neuroscience group additionally studies cognitive disorders caused by diseases such as stroke (cerebrovascular disease), Alzheimer's disease and other dementias from a clinical perspective.

All Labs that operate in this Division

Addiction Neuroscience LaboratoryDevelopmental Psychobiology LaboratoryEpigenetics and Neural Plasticity LaboratoryGenes Environment and Behaviour LaboratoryInhalant Addiction LaboratoryMidbrain Dopamine Plasticity LaboratorySynapse Biology and Cognition Laboratory