# Ultrastructure of the hippocampal trisynaptic pathway in schizophrenia

> **NIH NIH R21** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $185,625

## Abstract

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 schizophreni...

## Key facts

- **NIH application ID:** 10460239
- **Project number:** 5R21MH127513-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Rosalinda C Roberts
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $185,625
- **Award type:** 5
- **Project period:** 2021-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10460239

## Citation

> US National Institutes of Health, RePORTER application 10460239, Ultrastructure of the hippocampal trisynaptic pathway in schizophrenia (5R21MH127513-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10460239. Licensed CC0.

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