The Rebecca L Cooper Research Laboratories
Brian Dean

INTRODUCTION

Primary focus: schizophrenia, bipolar disorder, major depression

The Rebecca L Cooper Laboratory (RLC) focuses on identifying the molecular pathways that are affected by the pathophysiologies of
mental illness.

Understanding the pathophysiology of these diseases will enable
the development of rationale based drug design directed towards the proteins or RNA that are involved in disease processes.

Using this approach and postmortem human brain tissue from the Victorian Brain Bank Network the laboratory has made two notable recent discoveries.

Identifying a subgroup within patients with schizophrenia

Elizabeth Scarr and colleagues discovered a sub-group of around one quarter of subjects with schizophrenia who have lost approximately 75% of their cortical muscarinic M1 receptors.

The cortical M1 receptor is critical in maintaining the brain functioning required to make normal daily decisions. So people who have lost these receptors are likely to experience severe difficulties in organising their day
to day living.

The discovery:

• confirms the long held view that schizophrenia is a syndrome made up of different diseases; and
• suggests that a marker of one of these diseases is a marked loss of muscarinic M1 receptors in the cortex.

The Group are collaborating with the Melbourne Neuropsychiatry Centre to use neuroimaging to identify patients who have lost the majority of their cortical M1 receptors. Study people while they are alive will help us to fully understand the consequences of losing so many receptors.

Funds from the National Health and Medical Research Council (NHMRC) were used to compare changes in the expression of all known genes in the brains of:

• people with schizophrenia who have lost muscarinic receptors;
• people with schizophrenia who have not lost muscarinic receptors; and
• control subjects.

Researchers will also compare gene expression in mice engineered not to have muscarinic M1 receptors to that in wild type mice. The premise for these experiments is that muscarinic M1 knockout mice are a “biochemical
model” for what the group has termed Muscarinic Receptor Deficit Schizophrenia.

Other types of schizophrenia

Significant variation in the symptom profile of people diagnosed with schizophrenia suggests that they actually have at least four different diseases.Having separated 25% of subjects with schizophrenia into a biologically homogenous group, the challenge is to find markers to
separate the other 75% of subjects with schizophrenia into disease groups using other markers.

We plan to use our unique 2D electrophoresis technique to measure levels of 11,000 proteins at one time in the brains of people who had schizophrenia.

We will then work with The University of Melbourne Centre of Excellence for Mathematics and Statistics of Complex Systems to identify proteins that can be used to separate subjects with schizophrenia into distinct groups, these groups representing different forms of schizophrenia.

Proinflammatory Pathways and Depression

Because people with arthritis have a greater chance of getting depressed than people with other chronic illnesses, the RLC is working to see whether proinflammatory pathways might be over-active in the brains of people with depression.

Many studies using blood from subjects with depression have shown changes in inflammatory cytokines. However, Brian Dean and colleagues are the first to have shown a 150% increase in transmembrane tumour necrosis factor in the cortex of subjects with depression and bipolar disorder; an increase not apparent in schizophrenia.

Since tumour necrosis factor is a central molecule in the proinflammatory pathways, this suggests that they are indeed affected in depression. Researchers are now investigating which proinflammatory pathways are
altered and to what extent, in various areas of the brains of subjects with depression; and also whether current antidepressants impact on these pathways.