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