Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia

Abstract

The pathophysiology of schizophrenia may involve perturbations of synaptic organization during development. The presence of cytoarchitectural abnormalities that may reflect such perturbations in the brains of patients with this disorder has been well-documented. Yet the mechanistic basis for these features of the disorder is still unknown. We hypothesized that altered regulation of the neuronal growth-associated protein GAP-43, a membrane phosphoprotein found at high levels in the developing brain, may play a role in the alterations in brain structure and function observed in schizophrenia. In the mature human brain, GAP-43 remains enriched primarily in association cortices and in the hippocampus, and it has been suggested that this protein marks circuits involved in the acquisition, processing, and͞or storage of new information. Because these processes are known to be altered in schizophrenia, we proposed that GAP-43 levels might be altered in this disorder. Quantitative immunoblots revealed that the expression of GAP-43 is increased preferentially in the visual association and frontal cortices of schizophrenic patients, and that these changes are not present in other neuropsychiatric conditions requiring similar treatments. Examination of the levels of additional markers in the brain revealed that the levels of the synaptic vesicle protein synaptophysin are reduced in the same areas, but that the abundance of the astrocytic marker of neurodegeneration, the glial fibrillary acidic protein, is unchanged. In situ hybridization histochemistry was used to show that the laminar pattern of GAP-43 expression appears unaltered in schizophrenia. We propose that schizophrenia is associated with a perturbed organization of synaptic connections in distinct cortical associative areas of the human brain, and that increased levels of GAP-43 are one manifestation of this dysfunctional organization.Structural anomalies are present in the brains of patients with schizophrenia. In vivo neuroimaging techniques have demonstrated a significant ventricular enlargement and decrease in cortical mass that seem to be unrelated to the treatment of the disorder (1). Postmortem analyses of schizophrenic patients also show a reduction in the total brain volume, particularly in the cerebral cortex (2). Fine structural neuropathology also has been detected in the frontal and temporal lobes of schizophrenics (reviewed in refs. 3 and 4). Careful microscopic evaluation has revealed specific neuronal loss in the cingulate cortex (5-7), hippocampal formation, entorhinal cortex, and parahippocampal gyrus (8, 9), demonstrating for the first time the presence of cytoarchitectural aberrations in schizophrenia. The reduction in numbers of neuronal cells was not accompanied by reactive gliosis, as would have been expected for a neurodegenerative lesion occurring in adulthood. Although the cause of the specific cell loss remains unknown, the idea of schizophrenia as a neurodevelopmental disorder is an attractive hypothesis (3, 4, 10-17).The presen...

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

“…b-Tubulin has previously been used as internal control 52,53 and several studies have found expression of b-Tubulin to be unaffected in schizophrenic brain. 54,55 However, in order to further minimize the potential effect of dendritic loss on bTubulin expression, we used an antibody that recognizes not only the neuron-specific isoform III, but all b-Tubulin isoforms (I, II, III, IVa and IVb), representing both neuronal and non-neuronal tubulin expression. Examples of representative immunoblots are shown in Figure 1a.…”

The Human Brain Revisited Opportunities and Challenges in Postmortem Studies of Psychiatric Disorders

“…However, the distinctive features of such subjects constrains the extent to which findings from these studies can be generalized to other forms or earlier stages of the illness. Indeed, studies of elderly, chronically hospitalized subjects with schizophrenia have yielded some findings such as increased levels of synaptophysin protein in the prefrontal cortex (Gabriel et al 1997), that appear to be in the opposite direction to the decreased levels of this protein observed in studies of younger subjects with the disorder (Perrone-Bizzozero et al 1996;Glantz and Lewis 1997;Karson et al 1999). For most postmortem studies, especially of individuals in the early to mid-stages of a psychiatric disorder, who are most likely to die by suicide or by an accident or illness not apparently related to the primary disease process, such prospective, antemortem assessments are not possible.…”

Stereologic analysis of the lateral geniculate nucleus of the thalamus in normal and schizophrenic subjects

“…These abnormalities include increased neuronal cell packing density (Selemon et al, 1995), decreased expression of synaptophysin protein and mRNA (Perrone-Bizzozero et al, 1996;Eastwood et al, 2000), and decreased expression of RSG4 mRNA, a gene that regulates G-coupled intracellular signaling (Mirnics et al, 2001). All of these findings are consistent with reduced connectivity and diminished synaptic signaling in the visual cortex.…”