# Uncovering the role of SAP97 in synaptic function and schizophrenia.

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $451,331

## Abstract

PROJECT SUMMARY
 Preclinical and clinical data show elevated glutamatergic transmission and neuronal activity within the
hippocampus during the early stages of schizophrenia development, and it is proposed that such elevations drive
the progression of the disorder. However, the molecular and cellular mechanisms that give rise to schizophrenia-
related elevations in hippocampal glutamatergic transmission are unknown. Recent human genetic data supports
a connection between reduced DLG1 gene expression/function and schizophrenia. The DLG1 gene encodes
the putative synaptic regulatory protein SAP97. However, a clear synaptic regulatory role for SAP97 has
remained elusive. We have now, for the first time, identified a native synapse in the brain where SAP97 plays a
critical and direct role in synaptic regulation. The long-term goal of our research is to understand how
glutamatergic synapse dysfunction contributes to the development of psychiatric disorders. Our central
hypothesis is that disruption of SAP97 function in dentate granule neurons (DG neurons) of the hippocampus
produces pathological synaptic strengthening that contributes to schizophrenia etiology. Guided by strong
preliminary data, we will pursue this hypothesis in three specific aims. In Aim 1, we will combine
electrophysiological methods with brand new imaging tools to characterize pathway-specific roles of SAP97 in
regulating glutamatergic neurotransmission and plasticity. In Aim 2, we will use a combination of newly generated
antibodies, molecular biological and electrophysiological/imaging approaches to identify the roles of SAP97
subregions in governing SAP97’s subcellular localization and influence over glutamatergic synapse function in
DG neurons. In Aim 3, we will deploy cutting-edge in vivo imaging tools in freely behaving animals in order to
understand how hippocampal neuron activity is altered in rodents with compromised SAP97 function. The
present proposal is innovative because it deploys new and powerful genetic, in vivo imaging, and behavioral
analysis tools that will allow a precise characterization of a newly discovered role for SAP97 in regulating the
function of native glutamatergic synapses in the hippocampus. The proposal is significant because it stands to
identify synaptic pathology in a specific brain region that represents a common component in schizophrenia
development. This proposal squarely meets the mission objectives of the NINDS given its focus on
understanding glutamatergic synapse regulation and memory formation which are found to be disrupted in
complex brain disorders.

## Key facts

- **NIH application ID:** 10736790
- **Project number:** 1R01NS130185-01A1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Bruce Herring
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $451,331
- **Award type:** 1
- **Project period:** 2023-06-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10736790

## Citation

> US National Institutes of Health, RePORTER application 10736790, Uncovering the role of SAP97 in synaptic function and schizophrenia. (1R01NS130185-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10736790. Licensed CC0.

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