ALTERED SYNAPTOPHYSIN EXPRESSION AS A MARKER OF SYNAPTIC PATHOLOGY INSCHIZOPHRENIA

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 hybrid ization histochemistry and immunoreactivity to assess the expression o f synaptophysin messenger RNA and protein respectively in medial tempo ral lobe from seven schizophrenics and 13 controls. In the schizophren ic cases, synaptophysin messenger RNA was reduced bilaterally in CA4, CA3, subiculum and parahippocampal gyrus, with a similar trend in dent ate gyrus but no change in CAI. It was also decreased in terms of grai ns per pyramidal neuron in the affected subfields. In parahippocampal gyrus, the loss of synaptophysin messenger RNA per neuron in schizophr enia was greater in deep than superficial laminae. A parallel study in rats showed no effect of haloperidol treatment upon hippocampal synap tophysin messenger RNA, suggesting that neuroleptic treatment does not underlie the reductions found in schizophrenia. In the right medial t emporal lobe of schizophrenics, we confirmed the correlations of synap tophysin 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 cas es. Synaptophysin immunoreactivity in schizophrenia showed no signific ant 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 densit y, the data suggest that pyramidal neurons within the medial temporal lobe may form fewer synapses. However, the lack of any significant dif ferences in synaptophysin immunoreactivity despite the loss of encodin g messenger RNA means that this conclusion must be drawn cautiously. T here are several plausible explanations For the preservation of synapt ophysin immunoreactivity despite reductions in transcript abundance; o ne possibility is that the inferred loss of synapses occurs in extra-h ippocampal sites to which the affected pyramidal neurons project. For example, the reduction in synaptophysin messenger RNA in subicular neu rons may be accompanied by decreased density of synaptic terminals in the nucleus accumbens. Such differences in the efferent synaptic conne ctivity of the hippocampus have previously been hypothesized to be an important component of the circuitry underlying schizophrenia.