Evaluation of Dynamin Inhibitors as Novel Therapies for Epilepsy

Supervisors: Dr. Nigel Jones, Prof. Terry O’Brien, Prof. Phil Robinson

Background: The group of Phil Robinson at the CMRI have discovered the principle that dynamin modulators can control synaptic transmission. Consequently, they have engineered the first generation of small molecule dynamin inhibitors and have preliminary evidence for their effectiveness as anticonvulsant drug candidates using in vivo models. The GTPase activity of the enzyme dynamin is a novel molecular target for epilepsy. Blocking dynamin produces inhibition of neuronal synaptic vesicle endocytosis (SVE) and reduced synaptic transmission. The common feature of all anti-epileptic drugs (AEDs) is a reduction in synaptic transmission. For most AEDs the mechanistic basis of this reduction is uncertain. In a 2006 publication in Nature Neuroscience Professor Robinson’s group showed that inhibition of SVE by blocking dynamin leads to an activity-dependent run-down in synaptic transmission. The unique aspect of this discovery is the lack of effect on acute or brief bursts of synaptic transmission - being inhibited only after high or prolonged stimulation. We propose that molecules based on SVE inhibition would reflect a new and better AED design, especially in those cases where sufferers fail to respond to or tolerate conventional treatments.

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Examining Sez-6 function in the retina

We have created a mouse mutant without the Sez-6 gene. These mice have reduced electrical properties in their brains and this is correlated with their behavioural activities.

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Executive control of attentional networks across the lifespan: implications for neuropsychiatric and addictive disorders

Co-supervisor: Dr Ben Harrison

Over the past decade, The Melbourne Neuropsychiatry Centre has used the Multi-Source Interference Task (MSIT) in several functional MRI (fMRI) studies to examine brain networks underlying attentional control in healthy controls and clinical patients. We have now collected nearly 300 healthy controls (age range 16-55 years) and 300 clinical patients (with schizophrenia, bipolar disorder, depression, obsessive-compulsive disorder, as well as cannabis and opiate dependence).

A major challenge is that this data has been acquired across 3 different scanners and 2 different field strengths and slightly different parameters. The role of the PhD candidate will be to integrate this data in a way that enables analysis of the full dataset. Once this is achieved, the PhD candidate will then have rich and complex database and have the opportunity to ask many questions about normal and abnormal development and functioning of the brain networks underlying attentional control in healthy and clinical populations.

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Exploration of functional synchrony in brain networks using MRI

Supervisor(s) - Prof Graeme Jackson, Dr. David Abbott

Functional MRI (fMRI) has been used since the early 1990’s to image the brain’s response to specific stimuli. It is an MRI technique that makes use of an intrinsic contrast mechanism involving the different magnetic states of oxygenated and de-oxygenated haemoglobin. Recently it has been found that the blood-oxygenation level dependant (BOLD) fMRI signal measured whilst a subject is at “rest” contains low frequency (<0.08Hz) fluctuations that appear to be related to functionally connected networks. This project involves the development of novel image analysis strategies to maximise information extracted from resting state fMRI time series, and to help determine how these techniques can best be applied to improve our understanding of brain networks in the healthy and diseased brain.

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Factors regulating regeneration of dopamine neurones

We have found that remaining dopamine neurones are capable of regeneration and repair after a partial lesion (i.e. killing a proportion of the original population of dopamine cells).

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