# Determining the relationship between NAAG and memory deficits in schizophrenia in mid- to late- life

> **NIH MH R01** · JOHNS HOPKINS UNIVERSITY · 2026 · $699,926

## Abstract

Project Summary
Cognitive deficits are a core feature of schizophrenia and are particularly prominent in patients of advanced
age. In fact, schizophrenia patients are likely to experience worsening cognitive symptoms in mid- to late-life.
There is an abundance of evidence suggesting that targeting glutamate-mediated neurotransmission could
modulate neural connections that are responsible for the abnormal signaling and improve memory symptoms
of schizophrenia. GRM3, the gene that encodes the metabotropic glutamate receptor 3 (mGlur3), is a GWA-
associated risk gene for schizophrenia, and alterations in mGluR3 signaling change memory performance in
both animal models and humans. N-acetyl-aspartyl-glutamate (NAAG) is a peptide neurotransmitter that acts
as the only selective endogenous agonist of mGluR3. The amount of NAAG in the synapse is primarily
regulated by glutamate carboxypeptidase II (GCPII), which inactivates NAAG by cleaving the glutamate from
NAA. Increasing NAAG levels, through the inhibition of GCPII, may be effective for the treatment of memory
dysfunction in schizophrenia, as suggested by several animal models. This could be particularly relevant in
patients with schizophrenia in mid- to late-life, as GCPII levels are known to rise in the brain with aging.
However, there is a paucity of human data regarding the functional role of NAAG in cognition, and the
behavioral and neural consequences of human NAAG modulation is currently unknown. Before investing in the
development of a GCPII inhibitor, it is critical to determine the relationship between NAAG levels, memory
performance, and neural activity during memory in mid- to late-life. We propose to measure NAAG levels using
magnetic resonance spectroscopy in schizophrenia patients and healthy adults in mid- to late-life and to
correlate these NAAG levels with declarative and working memory performance (Aim 1) and neural activity
during memory tasks measured by functional MRI (Aim 2) in the same individual

## Key facts

- **NIH application ID:** 11352671
- **Project number:** 5R01MH137602-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** KRISTIN L BIGOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** MH
- **Fiscal year:** 2026
- **Award amount:** $699,926
- **Award type:** 5
- **Project period:** 2025-06-12T00:00:00 → 2030-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11352671

## Citation

> US National Institutes of Health, RePORTER application 11352671, Determining the relationship between NAAG and memory deficits in schizophrenia in mid- to late- life (5R01MH137602-02). Retrieved via AI Analytics 2026-07-14 from https://api.ai-analytics.org/grant/nih/11352671. Licensed CC0.

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