The Rebecca L Cooper Research Laboratories
Brian Dean

INTRODUCTION

The Rebecca L Cooper Laboratory aims to identify the molecular pathways that are involved in the pathologies of schizophrenia, bipolar disorder and unipolar depression.

By identifying the pathways involved in the genesis of these diseases we aim to discover new targets at which drug treatments can be directed. The Laboratory also aims to understand the mechanisms of actions of existing psychotropic drug treatments as a basis of developing improved treatments for schizophrenia and bipolar disorder.

HIGHLIGHTS

Muscarinic receptors

The core focus of much of the work of the group remains the role of muscarinic receptors in the pathology and treatment of schizophrenia. This work has now influenced the decision making of a number of pharmaceutical companies who are attempting to synthesise muscarinic receptor agonists, which our data suggests would be important to improving the symptoms of the disorder.

Most recently our research has shown that it is the muscarinic 4 receptor that is altered in the hippocampus of subjects with schizophrenia. This contrasts with our findings in another part of the human brain, the frontal cortex, where the muscarinic M1 receptor is most affected. Thus, we now know that there are complex changes in muscarinic receptors in the brains of subjects with schizophrenia and that drugs need to target both the M1 and M4 receptors.

Working with colleagues at the Howard Florey Institute we have recently shown that there are decreases in muscarinic receptors in mice that lack phospholipase ?1. We have also shown that housing these mice in 'enriched' conditions can reverse this loss of muscarinic receptors. This is very significant as schizophrenia is proposed to affect individuals with a genetic predisposition who are exposed to as yet unknown environmental factors. Our data now demonstrates, in mice, how the expression of muscarinic receptors can be affected by the combined effects of a genetic predisposition (the lack of the phospholipase ?1gene) and the environment. This is further evidence that changes in muscarinic receptors are critical to the development of schizophrenia.

Glutamate

The Laboratory has also been involved in collaborations with colleagues at the University of Alabama, showing that there are changes in the glutamatergic neurons in the brains of subjects with schizophrenia. In particular, this work has shown that there are changes in receptors sensitive to drugs such as phencyclidine (Angel dust) and ketamine in the hippocampus from subjects with schizophrenia.

Given that subjects who take such drugs can develop schizophrenia-like symptoms we believe our data is important in understanding which glutamate-sensitive pathways are affected by schizophrenia.

Gender variations

Following initial findings from 2D electrophoresis we have studied levels 14-3-3? in the CNS from subjects with schizophrenia and bipolar disorder. In the case of 14-3-3?, there was no difference in the levels of that signalling protein in the brains of subjects with psychiatric disease. However, for the first time, we showed that levels of that protein are markedly altered according to gender.It is known that gender is an important variable with regards to age of onset of schizophrenia and therefore our findings raise the possibility that changes of 14-3-3? between sexes may be involved in influencing the onset of the disorder.

Apolipoprotein E

We have recently published data to show that there are decreased levels of apolipoprotein E in the plasma of subjects with schizophrenia and bipolar disorder. This deficiency in apolipoprotein E was not affected by treatment with antipsychotic drugs but did seem to be partially reversed by treatment with mood stabilisers. We have proposed that changes in levels of plasma apolipoprotein E in subjects with schizophrenia and bipolar disorder may be associated with abnormal lipid homeostasis but further investigations are required to prove this hypothesis. It is significant that we have previously shown that levels of apolipoprotein E are altered in the brains of subjects with schizophrenia and bipolar disorder. This suggests abnormalities in the functioning of this protein may be affected in all tissue of the body.

Other work

International collaborations have continued with our colleagues in Israel. This work has shown that there are changes in signalling through the dopamine D2 receptor. This is an important finding as the drugs that are used to treat the psychotic symptoms of schizophrenia act to block the dopamine D2 receptor and this may also rectify the signalling abnormality we have identified in the brains of subjects with the disorder.

The work of the Rebecca L Cooper Research Laboratory is regularly accepted for publication in the top four psychiatric journals. In addition, the work of the Laboratory has been shown to be of interest to the general public when it was featured in the Channel 9 series, Suspicious Minds.

PERSONNEL

Brian Dean presented the Lilly Oration at the 2006 Scientific Meeting of the Australian Society for Psychiatric Research, was elected to the Council of the Collegium Internationale Neuro-Psychopharmacologium and also accepted an invitation to become an International Ambassador for the Society. He was also an invited panel member at the Australian Psychosis Research Network launch at Parliament House, Canberra.

Elizabeth Scarr won the Rotary Royce Abbey Postdoctoral Fellowship which she will commence in 2008. Simone Boer was awarded the Dame Margaret Guilfoyle Student Travel Award. Tammie Money was awarded a Rotary Scholarship in October 2006 and won a poster prize at the 2006 Scientific meeting of the Australian Society of Psychiatric Research.