Abnormal hippocampal synaptic connectivity in schizophrenia

The thesis was designed to address three major questions about the pathogenesis of schizophrenia. First, given findings of abnormal organisation of layer II and III neurons of the schizophrenic entorhinal hippocampus, would the perforant pathway ERC→hippocampal circuitry be altered? The investigation began by using improved methods of nonfluorescent immunocolocalisation and quantitative immunohistochemistry to assess the distribution and amount of presynaptic protein immunoreactivity [ir] (synaptophysin and SNAP-25; markers of synaptic density) in schizophrenia with normal controls. The perforant pathway termination zones in schizophrenia showed unchanged amounts of synaptophysin (an indirect indicator of synapses globally) and decreased amounts of SNAP-25 (enriched in a subset of synapses), suggesting that (a subset of) circuits from the entorhinal cortex to the hippocampus may be disconnected in schizophrenia. Second, given findings suggesting abnormal development in schizophrenia, would specific regions of the dentate gyrus (which have a different developmental profile) have altered circuitry in schizophrenia? Using optimised immunohistochemical image analysis of presynaptic proteins, schizophrenia showed that the number of terminals (as assessed by fractional area of immunostaining) was similarly increased for both limbs as gauged by synaptophysin ir and was more prominently reduced in the (later forming) internal limb than the (earlier forming) external limb of the dentate gyrus with SNAP-25 ir, which is consistent with the notion that schizophrenia may be a prenatal defect at 39-40 weeks gestational age (or earlier) when the two limbs should be identical - although differential postnatal properties between the limbs is also plausible. Thirdly, given that most schizophrenics are exposed to antipsychotic drugs (APDs), could the changes in presynaptic proteins seen here in schizophrenia be attributed to APD treatment? Using an approach to immunohistochemical image analysis parallel to the studies of schizophrenia, we studied presynaptic proteins (synaptophysin and SNAP-25) in rats exposed to typical APDs (haloperidol, chlorpromazine, and trifluperazine). Analysis of the ERC→hippocampal circuit after APD exposure generally revealed changes in presynaptic protein different in distribution and amount from that seen in schizophrenia. The results of this thesis indicate that schizophrenia may be a defect that results in aberrant synaptic reorganisation possibly arising from a prenatal developmental problem or from postnatal influences.Medicine, Faculty ofGraduat