P J Harrison1, S L Eastwood. 1. University Department of Psychiatry, Warneford Hospital, Oxford, UK. paul.harrison@psychiatry.ox.ac.uk
Abstract
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.
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.