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It has been proposed that synaptic density or synaptic innervation may be altered in schizophrenia as a correlate of the neurodevelopmental pathology of the disease. Synaptophysin is a synaptic vesicle protein whose distribution and abundance provides a synaptic marker which can be reliably measured in post mortem brain. We have used in situ hybridization histochemistry and immunoreactivity to assess the expression of synaptophysin messenger RNA and protein respectively in medial temporal lobe from seven schizophrenics and 13 controls. In the schizophrenic cases, synaptophysin messenger RNA was reduced bilaterally in CA4, CA3, subiculum and parahippocampal gyrus, with a similar trend in dentate gyrus but no change in CA1. It was also decreased in terms of grains per pyramidal neuron in the affected subfields. In parahippocampal gyrus, the loss of synaptophysin messenger RNA per neuron in schizophrenia was greater in deep than superficial laminae. A parallel study in rats showed no effect of haloperidol treatment upon hippocampal synaptophysin messenger RNA, suggesting that neuroleptic treatment does not underlie the reductions found in schizophrenia. In the right medial temporal lobe of schizophrenics, we confirmed the correlation of synaptophysin messenger RNA abundance between ipsilateral subfields seen in both hemispheres of control brains. However, these correlations were not observed in the left medial temporal lobe of the schizophrenic cases. Synaptophysin immunoreactivity in schizophrenia showed no significant differences in any subfield compared to controls. Our data support the broad hypothesis that synaptic pathology occurs in schizophrenia. In so far as synaptophysin expression is a marker for synaptic density, the data suggest that pyramidal neurons within the medial temporal lobe may form fewer synapses. However, the lack of any significant differences in synaptophysin immunoreactivity despite the loss of encoding messenger RNA means that this conclusion must be drawn cautiously. There are several plausible explanations for the preservation of synaptophysin immunoreactivity despite reductions in transcript abundance; one possibility is that the inferrred loss of synapses occurs in extra-hippocampal sites to which the affected pyramidal neurons project. For example, the reduction in synaptophysin messenger RNA in subicular neurons may be accompanied by decreased density of synaptic terminals in the nucleus accumbens. Such differences in the efferent synaptic connectivity of the hippocampus have previously been hypothesized to be an important component of the circuitry underlying schizophrenia.


Journal article



Publication Date





309 - 319


Animals, Biomarkers, Female, Gene Expression, Haloperidol, Histocytochemistry, Humans, In Situ Hybridization, Male, Middle Aged, Pyramidal Cells, RNA, Messenger, Rats, Schizophrenia, Synapses, Synaptophysin, Temporal Lobe