Behavioural Neuroscience Laboratory
Maarten van den Buuse

INTRODUCTION

Principal focus: schizophrenia, bipolar disorder, depression

The Behavioural Neuroscience Laboratory uses behavioural animal models to study neuropsychopharmacological mechanisms involved in schizophrenia.

We use state-of-the-art automated equipment for in vivo experiments, including photocell activity meters, automated video analysis of behaviour, prepulse inhibition of startle and models of learning and memory in rodents.

This in vivo work is complemented with human studies, neuropharmacological studies, including receptor autoradiography, and molecular studies.

HIGHLIGHTS

The ‘two-hit’ hypothesis of schizophrenia

This theory states that stress early in development increases vulnerability to later stressful events, rendering subjects at higher risk of developing psychosis.

Using aa ‘two-hit’ neurodevelopmental stress model in rats, Chris Choy showed two major changes in these animals:

• Regulation of prepulse inhibition, a test for brain sensory information processing, was characterised in these animals by a significant desensitisation to the neurotransmitter, dopamine.This would result in loss of flexibility and in the ability to respond to environmental stimulation.
• Selective cognitive deficits and reduced levels of brain-derived
  neurotrophic factor (BDNF, a growth factor that helps support existing neurons and encourages the growth and differentiation of new ones), in part of the brain involved in learning and memory, the hippocampus.

Maren Klug commenced a PhD project to further study the effects of neurodevelopmental stress on vulnerability markers for schizophrenia and depression.

This work is supported by a major new project grant from the National Health and Medical Research Council (NHMRC) and includes genetically-modified mice which only produce about half of the normal levels of BDNF.

Sally Martin established and maintains a breeding colony of these animals at MHRI. These mice are being treated with stress hormone and the long-term effects of this combined genetic and treatment approach are
characterised in a battery of behavioural tests, including learning and memory.

Oestrogen

Gender differences exist in schizophrenia with respect to:

• age of onset,
• severity of symptoms, and
• treatment response.

Andrea Gogos collaborated with Associate Professor Susan Rossell to publish findings on prepulse inhibition in bipolar disorder. She found that men with this illness tend to show disrupted prepulse inhibition, as has been reported by other groups around the world.

However, women with bipolar disorder were found to display higher prepulse inhibition compared to female control subjects. This surprising finding sheds new light on prepulse inhibition regulation in psychiatric illnesses and emphasises the importance of addressing gender in these studies.

Supported by a NHMRC project grant, Andrea Gogos and Perrin Kwek continued their pharmacological studies on the modulatory action of oestrogen and testosterone on behaviour and central neurotransmitter activity.

Carolina Chavez worked with geneticall ymodified mice which are unable to produce oestrogen and found marked reductions in responses to the psychostimulant, amphetamine.This indicates a major interaction of the altered hormonal state in these mice with regulation of behaviour by dopamine, a finding which could have implications for our understanding of
how oestrogen and other sex steroid hormones influence risk for schizophrenia and other psychiatric illnesses.

Serotonin

Wendy Adams found that rats with serotonin depletion in the dorsal
hippocampus show little change in cognitive function, despite showing markedly increased sensitivity to the effects of the hallucinogen, PCP.

Wendy also tested these animals for their sensitivity to a range of drugs of abuse. She found the involvement of dorsal hippocampus serotonin to be specific for PCP and the related ketamine. In contrast, psychostimulants
such as amphetamines and cocaine were not increased in their action.

hus, this rat model suggests a major involvement of dorsal hippocampus serotonin in some psychotic features of schizophrenia, such as delusions
and hallucinations, but not the cognitive deficits.

Meanwhile, Sally Martin showed that mice with large reductions of hippocampus serotonin levels have a similar enhanced response to phencyclidine to that seen in lesioned rats. The similarity between
our results in rats and mice will allow similar studies in genetically-modified mice.

Other studies focused on the role of the serotonin receptors in behavioural animal models of schizophrenia. Andrea Gogos published work on the differential involvement of the serotonin-1A receptor in the action
of antipsychotic drugs.

Sally Martin established a breeding colony of genetically-modified mice which are unable to produce this receptor. These animals will become highly valuable in projects on the role of the serotonin-1A receptor in schizophrenia and depression.

Rachel Hill introduced several new neurochemical methods in the laboratory. She commenced a project to study the interaction of serotonin-1A receptor function and BDNF. In parallel studies, she characterised mice which are unable to produce another serotonin receptor, the serotonin-2C receptor. Rachel demonstrated markedly elevated levels of BDNF
in the brains of these mice. However, initial behavioural characterisation of these animals revealed few changes and these studies are continuing.

Mouse models of schizophrenia and depression

Increasingly, the laboratory uses genetically-modified mice to address aspects of brain neurotransmitter involvement in schizophrenia and depression. In addition to BDNF mutant mice and knockout mice for serotonin-1A or serotonin-2C receptors, studies focused on the role of the cell signaling factor, CREB, or the schizophrenia risk gene, neuregulin-1.

In collaboration with Dr Theo Mantamadiotis at the Victorian College of Pharmacy, Sally Martin continued her studies to characterise behavioural and neurotransmitter changes in mice which are unable to produce CREB in the brain.

Neuregulin-1 mutant mice were obtained as Neuregulin-1 has been widely suggested to be a major risk factor in schizophrenia. Nevertheless, extensive behavioural and neuropharmacological characterisation of neuregulin-1 mutant mice failed to reveal clear evidence for such an involvement in models of psychosis and prepulse inhibition.

These important findings may have implications for the interpretation of human molecular genetic studies on neuregulin-1, although an involvement in other aspects of schizophrenia cannot be excluded.

Other published collaborative studies focused on mice with altered expression of the neurohormone angiotensin in the brain, and on mice with elevated expression of mutated synuclein, a protein involved
in Parkinson’s disease.

Glutathione

Levels of the endogenous radical scavenger, glutathione, are reduced in the brain in schizophrenia.

Olivia Dean showed that rats and mice with experimentally-induced glutathione depletion display deficient short-term spatial memory.
This finding may help to understand the involvement of oxidative stress in schizophrenia and the mechanisms by which drugs counteract oxidative stress may prove to be clinically beneficial.