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

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 individuals. We expect to 1) identify memory domains that are associated with differential NAAG levels, 2) identify memory task-related brain activity patterns that are regulated by NAAG, 3) determine if the relationship between NAAG and memory if changes from 35y to 65y, and 4) determine if the influence of NAAG on memory and brain function is greater in patients with schizophrenia in mid- to late-life compared to healthy adults. This proposal will therefore link variation in human NAAG levels with memory performance and brain function that would shed light onto the pathophysiology of memory dysfunction in schizophrenia in mid- to late-life and guide future development of treatments aimed at modulation of NAAG levels to improve memory symptoms. Furthermore, these findings will inform the future use of neuroimaging biomarkers in relevant clinical trials involving modulation of NAAG and mGluR3 for the treatment of memory dysfunction in mid- to late-life.