Current Molecular Medicine - Volume 3, Issue 5, 2003

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.

Schizophrenia and bipolar disorder remain two of the most severe and difficult to treat psychotic disorders hampered by our poor understanding of their pathologies. The development of typical antipsychotic drugs opened an avenue of investigation through the dopamine D2 receptor in schizophrenia. With the reintroduction of the atypical antipsychotic clozapine came the development of a new generation of atypical agents and hypotheses challenging the centrality of this receptor in explaining antipsychotic effects. Evaluation of these competing theories does not provide sufficient evidence to displace the importance of the dopamine D2 receptor in antipsychotic efficacy, but does raise limitations of it as an explanatory hypothesis. Further, the treatment of other symptom domains in schizophrenia remains relatively neglected and open for the development of novel therapies. Similar to schizophrenia, bipolar disorder presents a diversity of clinical states but unlike schizophrenia, its mainstay of treatment, lithium, has not had a clear receptor target impeding understanding of the disorder's pathology and treatment. This has pushed investigation into other domains emphasising a number of intracellular signalling pathways and glial-neuronal interactions. The heavy genetic loading of bipolar disorder has allowed linkage analyses to identify a number of putative regions, however, the diversity of phenotypes complicates such studies. Polymorphisms of candidate genes have yielded potential leads such as dopamine beta hydroxylase in mood disorder and the serotonin transporter for treatment response. It is anticipated that combining the above approaches may hold promise for the development of more effective treatments.

Apolipoprotein D (apoD) is an atypical plasma apolipoprotein and, based on its primary structure, it is a member of the lipocalin protein superfamily. Lipocalins have been extensively used as disease markers and, accordingly, apoD has become increasingly recognized as an important factor in the pathology of human neurodegenerative and neuropsychiatric disorders. ApoD expression is increased in the plasma and brains of subjects with schizophrenia and bipolar disorder, suggesting that it acts as a marker for disease pathology. ApoD also exhibits complex regulation by antipsychotic drug treatment and may represent a distinguishing mechanism of typical versus atypical drugs. The precise role of apoD in the CNS and disease remains to be elucidated, but recent findings have suggested that it plays an important role in the regulation of arachidonic acid signaling and metabolism providing further support for phospholipid membrane pathology in schizophrenia.

An increasing body of evidence suggests that the muscarinic receptors may present a potential therapeutic target for the treatment of schizophrenia. This argument is supported by studies using postmortem CNS tissue and a neuroimaging study that have shown there are regionally specific decreases in selective muscarinic receptors in the CNS of subjects with schizophrenia. This raises the possibility that drugs specific to individual muscarinic receptors could have beneficial effects on the symptoms of schizophrenia, a posit supported by studies in receptor knockout / knockdown mice where it has been shown that specific behaviours affected by schizophrenia are also abnormal in mice lacking a single muscarinic receptor. Moreover, drugs have been synthesised that are partial agonists at muscarinic receptors and these drugs have been shown to improve the behavioural deficits in humans which are modulated by the muscarinic receptor family. The widespread distribution of muscarinic receptors in the human CNS and the receptor specific changes identified in postmortem CNS from subjects with schizophrenia would suggest that drugs targeting specific muscarinic receptors would also need to partition into selected CNS regions to achieve optimal responses. Some existing compounds show regional selectivity for the same muscarinic receptor in different CNS regions, suggesting that this characteristic could be engineered into muscarinic receptor targeting drugs. This review presents data from diverse areas of research to argue that it is now imperative that the therapeutic potential of manipulating the activity of muscarinic receptors for the treatment of schizophrenia is fully explored.

The classification of schizophrenia and bipolar disorder as two separate disease entities has been hotly debated almost from the moment of its inception with Kraepelin's descriptions of “dementia praecox” and “manic-depressive insanity” in 1896. Kraepelin's nosologic distinction was based on clinical observation of symptomatology and outcome, and even today, despite major advances in science and technology, differential diagnosis of psychosis relies on the clinical course of illness. However, new evidence from diverse fields, e.g., genetics, neuropsychology, and brain imaging, have refueled the debate about whether or not schizophrenia and bipolar disorder represent distinct diseases, leading some to postulate that schizophrenia and bipolar disorder represent different manifestations of psychosis along a continuum with schizoaffective disorder representing an intermediate subtype. To this discourse, we add our own recent postmortem anatomic findings indicating that cellular pathology in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder differs not just in magnitude but also in direction, in laminar scope, and in relative involvement of neuronal and glial cell types. Thus, distinct morphometric alterations in the dorsolateral prefrontal cortex underlie what appear on neuroimaging analysis to be similar abnormalities in structural and metabolic function in the prefrontal cortex, and the diverse cellular pathology in the dorsolateral prefrontal cortex in these two disorders may account for the greater deficit in schizophrenia on cognitive tasks involving memory, problem solving and abstraction.

Neuropsychiatric disorders are generally diagnosed based on a classification of behavioral and, in some cases, specific neurological deficits. The lack of distinct quantitative and qualitative biological descriptors at the anatomical and cellular level complicates the search for and understanding of the neurobiology of these disorders. The advent of microarray technology has enabled large-scale profiling of transcriptional activity, allowing a comprehensive characterization of transcriptional patterns relating to the pathophysiology of neuropsychiatric disorders. We review some of the unique methodological constraints related to the use of human postmortem brain tissue in addition to the generally applicable requirements for microarray experiments. Microarray studies undertaken in neuropsychiatric disorders such as schizophrenia and substance abuse by the use of postmortem brain tissue indicate that transcriptional changes relating to synaptic function and plasticity, cytoskeletal function, energy metabolism, oligodendrocytes, and distinct intracellular signaling pathways are generally present. These have been supported by microarray studies in experimental models, and have produced multiple avenues to be explored at the functional level. The quality and specificity of information obtained from human postmortem tissue is rapidly increasing with the maturation and refinement of array-related methodologies and analysis tools, and with the use of focused cell populations. The development of experimental models of gene regulation in these disorders will serve as the initial step towards a comprehensive genome-linked analysis of the brain and associated disorders, and help characterize the integration and coordinate regulation of complex functions within the CNS.

In terms of impact on and cost to society psychiatric disorders are among the most important health problems of today. Current estimates from the US suggest that the collective cost of psychiatric diseases could amount to one-third of the total health care budget with a cumulative lifetime prevalence of 30%. While undoubtedly improvements have been made in the diagnosis and treatment of at least the symptoms of mental illness, there has been frustratingly little progress in elucidating the molecular mechanisms. However, a fundamentally different approach to study molecular mechanisms of psychiatric diseases is emerging as a result of technological advances in expression profiling methods. This comprises the investigation of the expressed disease ‘phenotypes’, developing from the differential gene and protein expression in the central nervous system as a result of the complex interaction between genetic predisposition and environmental modulation. This paper will focus on proteomics, expression profiling at the protein level, reviewing some of the available tools and their application in the molecular analysis of psychiatric disease.

Epidemiological studies have shown increased incidence of schizophrenia in patients subjected to different forms of pre- or perinatal stress. However, as the onset of schizophrenic illness does not usually occur until adolescence or early adulthood, it is not yet fully understood how disruption of early brain development may ultimately lead to malfunction years later. In order to elucidate a possible role for neurodevelopmental factors in the pathogenesis of schizophrenia and to highlight potential new treatments, animal models are needed. Prepulse inhibition (PPI) is a model of sensorimotor gating mechanisms in the brain. It is disrupted in schizophrenia patients and the disruption can be reversed with atypical antipsychotics. It has been widely used in animal studies to explore central mechanisms possibly involved in schizophrenia. There has been a recent surge of behavioural and neurochemical animal studies on neurodevelopmental models, particularly on the effects of postweaning isolation, maternal separation and neonatal lesions of the hippocampus. In these models, long lasting alterations in behaviour and / or molecular changes in specific brain regions are observed, comparable to those seen in schizophrenia. The aim of this article is to critically review the available literature on such neurodevelopmental animal models with special focus on the effects on PPI and brain regions that are putatively involved in regulation of PPI.

Mood disorders and schizophrenia share a number of common properties, including: genetic susceptibility; differences in brain structure and drug based therapy. Some genetic loci may even confer susceptibility for bipolar mood disorder and schizophrenia, and some atypical antipsychotic drugs are used as mood stabilizers. As schizophrenia is associated with aberrant neurodevelopment, could this also be true for mood disorders? Such changes could arise pre- or post-natal, however the recent interest in neurogenesis in the adult brain has suggested involvement of these later processes in the origins of mood disorders. Interestingly, the common mood stabilizing drugs, lithium, valproic acid (VPA) and carbamazepine, are teratogens, affecting a number of aspects of animal development. Recent work has shown that lithium and VPA interfere with normal cell development, and all three drugs affect neuronal morphology. The molecular basis for mood stabilizer action in the treatment of mood is unknown, however these studies have suggested both targets and potential mechanisms. Lithium directly inhibits two evolutionarily conserved signal transduction pathways: the protein kinase Glycogen Synthase Kinase-3 (GSK-3) and inositol signaling. VPA can up-regulate gene expression through inhibition of histone deacetylase (HDAC) and indirectly reduce GSK-3 activity. VPA effects are not conserved between cell types, and carbamazepine has no effect on the GSK-3 pathway. All three mood stabilizers suppress inositol signaling, results further supported by studies on the enzyme prolyl oligopeptidase (PO) and the sodium myo-inositol transporter (SMIT). Despite these intriguing observations, it remains unclear whether GSK-3, inositol signaling or both underlie the origins of bipolar disorder.