Glutamatergic pharmacology and receptor modifications underlying cognitive function in a rodent model of schizophrenia

Cognitive deficits are recognised as being a core symptom of psychiatric disorders including schizophrenia. Support for the N-methyl-D-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia has led to increasing focus on restoring proper glutamatergic signalling as an approach for treatment and the development of novel antipsychotics (see Neill et al., 2010). A number of animal models are available to study the neurobiological basis of psychiatric disorders and in particular schizophrenia. One such model is the Phencyclidine (PCP)-induced model of schizophrenia. PCP is a non-competitive NMDA receptor antagonist, which can induce a psychotic state that has some similarities to schizophrenia. Addressing cognitive dysfunction in schizophrenia remains a clinical unmet need.

More recently, research has focussed on the ability of metabotropic glutamate receptors (mGluRs) to modulate glutamatergic neurotransmission and thus improve cognition, particularly the Group 1 and 2 glutamate receptors; opening up new avenues for development of novel therapeutics. However, like all neurotransmitter receptors, mGluRs are subject to regulation by post-translational modifications, trafficking and degradation. Currently, regulation of mGluRs in schizophrenia and animal models of schizophrenia are poorly understood and remain to be elucidated. These are fundamentally important processes for normal neuronal function. Perturbations to these processes; and in particular, degradative systems and the resulting protein aggregations are implicated in a wide range of neuropsychiatric conditions. Receptor protein degradation occurs via their sorting (after ubiquitination) into intralumenal vesicles of late endosomes to form multivesicular bodies (MVBs) and subsequent fusion with lysosomes, targets these proteins for degradation. This initial sorting event is primarily mediated by large protein complexes known as Endosomal Sorting Complex Required for Transport (ESCRTs). Misregulation and mutations in ESCRT proteins and their interacting endosomal proteins have been linked to many neurological diseases. The stability of a protein is regulated by post-translational modification such as ubiquitination following stimulus and subsequent degradation. ESCRT complex proteins regulate the stability of receptors at the cell surface and in neurons, ESCRT proteins also play a crucial role in synapse formation and function by regulating spine development and dendrite pruning. We hypothesise that the widely used PCP-model has altered expression of mGluR’s and that by modulating this altered expression/activity through small molecule application or receptor expression (through virus) we can alleviate the damaging effects of PCP.

The aims of this project are to:
• Determine the expression of glutamate and GABA receptors and their modifications following acute and sub-chronic PCP animal models and to correlate these changes to cognitive performance
• Utilise selective mGluR pharmacological agents to improve cognition in the sub-chronic PCP model and to assess the effects on receptor expression following acute and chronic (21 day) treatment
• Utilise lenti-viruses to overexpress/knockdown ESCRT subunits in vivo to perform biochemical assays, elucidating the trafficking and degradation of mGlu receptors following PCP.