Preface

In the opening sentence of their preface to the Third Edition of The Principles of Neural Science, Eric Kandel, James Schwartz and Thomas Jessell state, “The goal of neural science is to understand the mind, how we perceive, move, think and remember”. It is significant that the stated goal of neural science is to understand the “mind” rather than the brain when the goal is to understand the higher functions that we attribute to that important organ of the body. Similarly, diseases such as schizophrenia and bipolar disorder, which predominantly affect the higher functions of the brain, are commonly regarded as diseases of the mind. In his book The History of Psychiatry, Edward Shorter argues that the care of individuals regarded as having diseases of the mind began to pass into the hands of a discrete body of physicians, the psychiatrists, in the mid-eighteenth century. Since that time, whilst concepts on diagnosis of these illnesses have evolved and drugs to treat the symptoms of psychiatric illnesses have been developed, little has been elucidated about the pathological processes leading to the onset of the disorders. This edition of Current Molecular Medicine will focus on current ideas and methodological approaches to understanding disorders that have remained a mystery to neuroscience. Ironically, it may be an understanding of the neurobiology of psychiatric disorders that leads us to an understanding of how we perceive, move, think and remember, the proposed central goal of neural science. This issue of the journal will focus on two major psychiatric disorders, schizophrenia and bipolar disorder. Sundram and colleagues open the volume by providing a perspective on the central symptomatology that is still used to diagnose schizophrenia and bipolar disorder in the absence of any proven biological marker. They also review the current understanding of the actions of drugs used to treat schizophrenia and bipolar disorder, thus highlighting the irony that compounds are used to treat disorders that have an unknown genesis and that it is not clear as to how these drugs produce their therapeutic benefits. This contrasts with a number of neurological disorders which have a well defined pathology but lack effective therapeutic agents. Having defined the disorders that are the focus of this volume the remainder of the volume will focus on three main areas. The first papers will review discrete bodies of evidence that suggest that particular proteins or cellular systems may be involved in the pathological processes underlying schizophrenia and bipolar disorder. These papers will be followed by two papers outlining how newly developed high-throughput screening technologies are impacting on our understanding of the pathologies of psychiatric illnesses. Finally, two papers will describe how animal models can be used to understand the mechanism that can either underpin the pathology of psychiatric illness or help understand how drugs achieve their therapeutic outcomes. In the first of the papers reviewing potential roles for particular proteins in the pathology of schizophrenia and bipolar disorder, Thomas and colleagues will review the potential role of apolipoprotein D (apoD) in the pathologies of schizophrenia and bipolar disorder. ApoD is a member of the lipocalin protein family and is not structurally related to the family of apolipoprotein E proteins that have been implicated in the pathology of other disorders such as Alzheimer's disease. Evidence will be presented that implicates apoD in both the pathologies of schizophrenia and bipolar disorder as well as the actions of antipsychotic drugs. Whilst it will be acknowledged that the precise role of apoD in the brain and in the pathologies of disease remains to be elucidated, changes in the protein as observed in schizophrenia would support a role for phospholipid membrane pathology in that disorder. Focussing on schizophrenia, Dean and colleagues will review a growing body of evidence that suggests a role for the muscarinic family of receptors in both the pathology of schizophrenia and the actions of antipsychotic drugs. This hypothesis will be supported by data from the study of postmortem human brain tissue, human neuroimaging studies and findings in animal knock out models that lack one of the five members of the family of muscarinic receptors present in the human brain. A new model as to why atypical antipsychotic drugs may be having an unexpected affect at muscarinic receptors will also be developed and will be a model against which future data on this topic can be tested. Moving from the molecular to the cellular, Selemon and Rajkowska will argue that disease-specific changes in the architecture of the dorsolateral prefrontal cortex provide a mechanism to delineate the pathologies of schizophrenia and bipolar disorder. Significantly, they will argue that the changes observed in the cortex from subjects with schizophrenia may account for the greater deficit in cognitive tasks involving memory, problem solving and abstraction observed in subjects with the disorder. This would add to the argument that schizophrenia and bipolar disorder do display separate pathologies and are therefore discrete disease entities. Focus then moves from classic hypothesis driven approaches to understanding the pathologies of schizophrenia and bipolar disorder to reviews of the impact of high-throughput screening on our understanding of psychiatric disease. In the first of these papers Lehrmann and colleagues review findings from the use of microarrays, a methodology that can measure levels of thousands of messenger RNAs at one time, to study levels of gene expression in postmortem human brain tissue. A careful consideration of the methodological consideration involved in using microarrays to examine gene expression in postmortem human brain tissue is followed by an extensive review of studies using this approach to understanding the pathology of schizophrenia. In summarising these data it is argued that changes in synaptic function and plasticity, cytoskeletal function, energy metabolism, oligodendrocytes, and distinct intracellular signaling pathways are important in the pathology of schizophrenia. Moving from gene expression to protein levels Voshel and colleagues will outline the use of different technologies that can be used to measure the levels of thousands of proteins at one time in postmortem human brain tissue. Methodological problems surrounding such approaches are outlined and the limited numbers of studies in this area relating to schizophrenia are reviewed. Attempts to understand the mechanisms underlying the pathologies of psychiatric illnesses have long involved the use of animal models. van den Buuse and colleagues have focussed on prepulse inhibition (PPI) as a model of sensorimotor gating mechanisms in the brain that has also been shown to be disrupted in schizophrenia. Significantly, abnormalities in PPI can be reversed with atypical antipsychotics and therefore there is great scope for using this model to understand both the pathology and psychopharmacology of the disorder. In 1949 John Cade, a Melbourne Psychiatrist, published the first study on the use of lithium in the treatment of psychiatric illness. Lithium still remains a drug that is used extensively as a mood stabiliser in the treatment in bipolar disorder. However, whilst lithium is well known as a mood stabilizer it also has effects on neurodevelopment which has implications for understanding the pathology of bipolar disorder. Thus, in the final paper in this volume, Harwood focuses on the use of mood stabilizers as teratogens that affect a number of processes during animal development. Highlighted will be current knowledge of the target pathways for mood stabilisers and whether changes in the activity of these pathways could explain the origins of mood disorders or reveal the basis for drug therapy.