Preferential involvement of excitatory neurons in medial temporal lobe in schizophrenia

BACKGROUND The anatomical basis of schizophrenia involves the cytoarchitecture of the cerebral cortex, but the phenotype of the affected neurons and synapses remains unclear. In mice, the presynaptic protein complexin I is a marker of axosomatic (inhibitory) synapses, whereas complexin II is a marker of axodendritic (mainly excitatory) synapses. These findings suggest that the complexins might be useful in the investigation of the synaptic pathology of schizophrenia. METHODS We characterised the expression of the complexins in tissue taken at necropsy from human medial temporal lobe (hippocampus, parahippocampal gyrus) and cerebellum using in-situ hybridisation and immunoautoradiography. We then measured the concentrations of the complexins and their messenger RNAs (mRNAs) in the medial temporal lobe of 11 patients with schizophrenia and 11 non-schizophrenic controls. FINDINGS The distribution of complexin I and II was consistent with the data on mice, with predominant expression of complexin I by inhibitory neurons, and complexin II by excitatory neurons. The amounts of both complexin mRNAs were lower in schizophrenic than in control patients (p<0.001), but the difference of complexin II mRNA was greater. The amount of complexin I protein was unchanged in schizophrenia, but complexin II protein was decreased (p<0.001). For both mRNA and protein, the complexin II/complexin I ratio was lower in schizophrenia, confirming the relatively greater loss of the excitatory marker. The findings did not seem attributable to medication. INTERPRETATION The synaptic pathology of schizophrenia, at least in medial temporal lobe, primarily affects excitatory (glutamatergic) neurons. The inferred imbalance between excitatory and inhibitory circuitry may contribute to the involvement of this region in the pathophysiology of the disorder.

[1]  T. Woo,et al.  A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[2]  J. Trojanowski,et al.  Recent advances in defining the neuropathology of schizophrenia , 1996, Acta Neuropathologica.

[3]  Paul J. Harrison,et al.  The hippocampus in schizophrenia: lateralized increase in neuronal density and altered cytoarchitectural asymmetry , 1997, Psychological Medicine.

[4]  S. Hirsch,et al.  Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia , 1998, Journal of neurology, neurosurgery, and psychiatry.

[5]  R. Kerwin,et al.  Alterations in hippocampal non-phosphorylated MAP2 protein expression in schizophrenia , 1997, Brain Research.

[6]  C. Frith,et al.  Disordered functional connectivity in schizophrenia , 1996, Psychological Medicine.

[7]  F. Benes,et al.  Reduced neuronal size in posterior hippocampus of schizophrenic patients. , 1991, Schizophrenia bulletin.

[8]  Paul J. Harrison,et al.  Size, shape, and orientation of neurons in the left and right hippocampus: investigation of normal asymmetries and alterations in schizophrenia. , 1997, The American journal of psychiatry.

[9]  S. Heckers,et al.  Hippocampal neuron number in schizophrenia. A stereological study. , 1991, Archives of general psychiatry.

[10]  J Q Trojanowski,et al.  Abnormal expression of two microtubule-associated proteins (MAP2 and MAP5) in specific subfields of the hippocampal formation in schizophrenia. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Paul J. Harrison,et al.  Distribution of kainate receptor subunit mRNAs in human hippocampus, neocortex and cerebellum, and bilateral reduction of hippocampal GluR6 and KA2 transcripts in schizophrenia , 1997, Brain Research.

[12]  P Falkai,et al.  SNAP-25 deficit and hippocampal connectivity in schizophrenia. , 1998, Cerebral cortex.

[13]  Paul J. Harrison,et al.  Decreased hippocampal expression of a glutamate receptor gene in schizophrenia , 1991, The Lancet.

[14]  Paul J. Harrison,et al.  Decreased synaptophysin in the medial temporal lobe in schizophrenia demonstrated using immunoautoradiography , 1995, Neuroscience.

[15]  R. Freedman,et al.  Significant reductions in synapsin but not synaptophysin specific activity in the brains of some schizophrenics , 1993, Biological Psychiatry.

[16]  Paul J. Harrison,et al.  Altered synaptophysin expression as a marker of synaptic pathology in schizophrenia , 1995, Neuroscience.

[17]  S. Lawrie,et al.  Brain abnormality in schizophrenia , 1998, British Journal of Psychiatry.

[18]  R. Saunders,et al.  A qualitative and quantitative analysis of the entorhinal cortex in schizophrenia. , 1997, Cerebral cortex.

[19]  Paul J. Harrison,et al.  The relative importance of premortem acidosis and postmortem interval for human brain gene expression studies: selective mRNA vulnerability and comparison with their encoded proteins , 1995, Neuroscience Letters.

[20]  J. Kleinman,et al.  Abnormal excitatory neurotransmitter metabolism in schizophrenic brains. , 1995, Archives of general psychiatry.

[21]  P. Slater,et al.  Frontal Cortical and Left Temporal Glutamatergic Dysfunction in Schizophrenia , 1989, Journal of neurochemistry.

[22]  Thomas C. Südhof,et al.  Complexins: Cytosolic proteins that regulate SNAP receptor function , 1995, Cell.

[23]  H. Kaba,et al.  Identification of two highly homologous presynaptic proteins distinctly localized at the dendritic and somatic synapses , 1995, FEBS letters.

[24]  K. Davis,et al.  Increased concentrations of presynaptic proteins in the cingulate cortex of subjects with schizophrenia. , 1997, Archives of general psychiatry.

[25]  J. Olney,et al.  Glutamate receptor dysfunction and schizophrenia. , 1995, Archives of general psychiatry.

[26]  S. Palay,et al.  The morphology of synapses , 1996, Journal of neurocytology.

[27]  D. Weinberger,et al.  From neuropathology to neurodevelopment , 1995, The Lancet.

[28]  J. Trojanowski,et al.  Smaller neuron size in schizophrenia in hippocampal subfields that mediate cortical-hippocampal interactions. , 1995, The American journal of psychiatry.