Ultrastructure of the hippocampal trisynaptic pathway in schizophrenia

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Schizophrenia (SZ) is a devastating mental illness with genetic and environmental risk factors that affects 1% of the world population. Pathology exists in multiple grey and white matter areas and neurotransmitter systems, making the search for a cause(s) and effective treatment elusive. Exploring new pathological mechanisms is paramount in trying to advance our understanding of SZ. The hippocampus is considered to play a pivotal role in the neuropathology and physiology of schizophrenia. Though widely studied, there have been inconsistencies in which subregions, neurotransmitters and cell populations are affected; thus how specific subregion abnormalities contribute to disease expression remain to be fully determined. This proposal aims to identify the circuitry that contribute to region-specific imbalances in excitation and inhibition in the hippocampus in schizophrenia. Here, we propose to test whether there are region-specific differences in the excitatory and inhibitory synapses in the trisynaptic pathway in postmortem tissue of patients with schizophrenia compared to a comparison group using quantitative electron microscopy. My overall hypothesis is two fold: 1) synaptic efficacy of excitatory synapses is enhanced by increased number or size of synapses or increased mitochondrial content in the terminals forming these synapses; and 2) the synaptic efficacy of inhibitory synapses in diminished by decreased number or size of synapses or decreased mitochondrial content in the terminals forming these synapses. Preclinical and clinic data indicate hyperactivity in the hippocampus that precedes the onset of psychosis, and which is correlated with the severity of symptoms. In our preliminary data, we have observed increased numbers of excitatory synapses and decreased number of inhibitory synapses, identified by morphological criteria. SA1) In postmortem brain, we will test the hypothesis that SZ cases have decreased efficacy of inhibitory synapses and an increased efficacy of excitatory synapses in the trisynaptic pathway by counting, measuring and categorizing the morphology of synapses and the mitochondria within the terminals forming them. SA2) To determine the synaptic density on the neuronal somata in the trisynaptic pathway. By examining the exact laminar location of excitatory inputs we will be able to determine the sources of abnormal circuitry. Electron microscopy offers the unique opportunity to measure hippocampal subfields in a layer and cell specific way at the level of the synapse. The source of afferent inputs to specific subfields and layers, the density of specific inputs, and the ultrastructural features of the axon terminals, the experiments in this application have the potential to reveal specific circuitry underlying hyperactivity in the hippocampus in schizophrenia and guide future tests of region and/or cell-specific interventions. Quantitative electron microscopic studies of the human postmortem hippocampus in schizophrenia currently are performed in only one other lab in the world. Our results on the ultrastructural results will have distinct functional implications for schizophrenia as well as for normal human hippocampal circuitry.