Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

Abstract

This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a 'genetic cytoarchitecture' would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications. Molecular Psychiatry (2005) 10, 40-68.

Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia

“…This developmental pattern is in accordance with the available data that early and transient disruptions in the developmental programs during brain development can produce a behavioral disease that manifests in adulthood. 6,61 Inducible expression of mutant hDISC1 in forebrain region resulted in a number of behaviors that have been associated with schizophrenia. 1,2,62 Intriguingly, the behavioral effects of mutant hDISC1 were sex dependent.…”

“…3,4 Numerous genetic linkage and association studies have identified regions of the genome that may harbor schizophrenia risk genes, but the complex genetics and symptomatology of the disease have impeded efforts to identify clear genetic determinants. 5,6 An alternative approach is to study families in which schizophrenia and allied psychiatric disorders segregate with cytogenetic abnormalities. 7 In these families, a single major genetic defect could confer susceptibility to psychiatric illnesses.…”

Phospholipase C-β1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration

“…tions ( Figure 5b; F (1,14) = 5.7, P < 0.05) with KOSH animals showing a significant reduction in [ 3 H]pirenzepine binding in comparison to WTSH (P < 0.05).…”

“…These and other findings suggest that this brain disorder arises from a genetic predisposition affecting neurodevelopmental processes, combined with exposure to environmental risk factors. 14 The complexity of the underlying physiological basis is highlighted by the multitude of pathways that have been implicated in pathogenesis including those involving dopaminergic, 15,16 serotonergic, 17,18 muscarinic [19][20][21][22] and glutamatergic signaling pathways. [23][24][25] It is, therefore, significant that PLC-b1 represents a point of convergence for these signaling pathways and that levels of the protein have been shown to be altered in the cortex of chronic schizophrenic patients, increasing in the prefrontal cortex and decreasing in the superior temporal gyrus.…”

Impact of complex genetic variation in COMT on human brain function

“…Due to the paucity of dopamine transporters in prefrontal cortex (PFC), 6 COMT is a critical determinant of prefrontal dopamine flux. 7 The gene is located at 22q11.2, a region implicated in schizophrenia by linkage 8 and by the 22q11.2 syndrome (MIM#192430), a hemideletion associated with strongly increased risk of schizophrenia-like illness. 9 A common val 108/158 met substitution affects the stability of the protein and leads to a significant decrease in the activity of the enzyme in brain and lymphocytes.…”