Catching up on schizophrenia: natural history and neurobiology

These research findings provide new opportunities and new challenges to understanding and treating schizophrenia. Certainly, a major challenge is to determine the genetic susceptibilities and pathogenetic mechanisms that can produce the complex clinical phenotype of schizophrenia. The identification of pathways of dysfunction, such as thalamo-prefrontal circuitry or the connections linking other cortical, subcortical, and cerebellar regions implicated in schizophrenia, permits studies of the relationships among the various alterations in a circuit and the elucidation of a putative endophenotype. For example, does a given abnormality represent a primary brain disturbance due to a causal factor of the disorder, or does it reflect a downstream pathologic consequence of the primary brain disturbance or an adaptive response that attempts to normalize the function of the circuit?Answers to these types of questions may create new opportunities for research at the intersection between systems level investigations and genetic approaches. Current views hold that schizophrenia is probably a consequence of multiple interacting genes; individually, these genes may have relatively little independent influence, and they may not all be involved in every individual who meets diagnostic criteria for the illness. Thus, assessment of the patterns of altered gene expression in the affected brain circuits of subjects with schizophrenia (using cDNA microarray technology or related techniques), and comparison of the chromosomal locations of these genes with regions implicated in schizophrenia through linkage studies (Pulver 2000xSearch for schizophrenia vulnerability genes. Pulver, A.E. Biol. Psychiatry. 2000; 47: 221–230Abstract | Full Text | Full Text PDF | PubMed | Scopus (99)See all ReferencesPulver 2000), may provide convergent approaches to the identification of specific vulnerability genes. For example, a recent study of gene expression profiling in the dorsal PFC of subjects with schizophrenia revealed that, of over 250 gene groups, the group of genes encoding proteins involved in the regulation of presynaptic function were most consistently altered (Mirnics et al. 2000xMolecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Mirnics, K., Middleton, F.A., Marquez, A., Lewis, D.A., and Levitt, P. Neuron. 2000; 28: 33–67Abstract | Full Text | Full Text PDFSee all ReferencesMirnics et al. 2000). Although the subjects with schizophrenia appeared to share a common abnormality in the control of synaptic transmission, the specific combinations of genes involved in presynaptic function that showed reduced expression differed among them. Interestingly, a number of the chromosomal loci that have been implicated in schizophrenia contain genes encoding proteins related to presynaptic function (Mirnics et al. 2000xMolecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Mirnics, K., Middleton, F.A., Marquez, A., Lewis, D.A., and Levitt, P. Neuron. 2000; 28: 33–67Abstract | Full Text | Full Text PDFSee all ReferencesMirnics et al. 2000).Recent research suggests that the heterogeneous phenotype of schizophrenia may be the result of multiple pathophysiological processes occurring at different stages of the illness (Lieberman 1999xIs schizophrenia a neurodegenerative disorder?. Lieberman, J.A. Biol. Psychiatry. 1999; 46: 729–739Abstract | Full Text | Full Text PDF | PubMed | Scopus (296)See all ReferencesLieberman 1999). These can be further characterized using multiple investigative approaches including in vivo neuroimaging, genetics, molecular neuropathology, and the development of animal models. Although animal models can only approximate the complex clinical phenotype of schizophrenia, they are essential to understand the molecular and cellular mechanisms that underlie the pathogenesis and pathophysiology of schizophrenia and can be used to test predictions from direct investigations of the illness. For example, conditional knockouts can be used to assess the consequences, at different stages of development, of the deficient expression of genes observed in subjects with schizophrenia. Therapeutic strategies based on this knowledge offer the promise of more effective interventions (including secondary and tertiary prevention), reduced morbidity, and better outcomes for patients.Thus, it should be apparent that although great progress has been made in catching up on schizophrenia, much remains to be done.‡To whom correspondence should be addressed (e-mail: lewisda@msx.upmc.edu [D. A. L.], jlieberman@css.unc.edu [J. A. L.]).