Project Summary/Abstract The number of elderly individuals over 65 years of age is projected to increase exponentially over the next several decades. Neurodegenerative diseases including Alzheimer’s and dementia are expected to pose a significant health and financial concern for aging individuals, their families, and society. In order to therapeutically combat neurodegenerative diseases, we have to understand age-associated alterations and delineate the mechanisms causing cognitive deficiency. Cognitive impairment in the form of reduced executive function, including attentional abilities and cognitive flexibility, is a characteristic of several psychiatric and neurodegenerative diseases as well as of cognitive aging. N-methyl-D-aspartate receptor (NMDAR) hypofunction contributes to impaired attention in schizophrenia. Furthermore, electrophysiological evidence has shown that NMDAR hypofunction in the medial prefrontal cortex (mPFC) emerges during middle age and is associated with a decline in attentional ability. Results indicate that like older humans, serine racemase RNA (SRR) declines in the mPFC of older rats with impaired cognition. Serine racemase generates D-serine, a co- agonist that regulates NMDAR function. The overall goal of this proposal is to test the hypothesis that enhancing NMDAR function through 1) upregulation of the GluN2B NMDAR subunit or 2) increased expression of SRR, in the mPFC, will restore NMDAR-mediated synaptic function and ameliorate attention and cognitive flexibility. Aim 1 will test the hypothesis that upregulation of the GluN2B subunit of NMDAR in the mPFC will restore NMDAR- mediated synaptic function and improve cognitive function. By employing specific expression vectors, we will limit the expression of the GluN2B subunit of NMDAR either to mPFC pyramidal neurons alone or in conjunction with interneurons. Behavioral performance of animals will be tested on the 5-choice serial reaction time task and the set-shifting task, and upregulation will be confirmed using electrophysiological, immunohistochemical, Western blotting, and RT-qPCR analyses. It is predicted that upregulation of GluN2B expression in the mPFC will restore NMDAR-mediated synaptic function and improve executive function. Aim 2 will test the hypothesis that a viral vector mediated increase in the expression of serine racemase, specific to pyramidal neurons or astrocytes will enhance NMDAR function and reverse cognitive deficits associated with senescence. Augmented expression, specific to pyramidal cells or astrocytes in the mPFC will be confirmed. We predict that upregulation of serine racemase will enhance NMDAR function and ameliorate attention and cognitive flexibility. The proposed studies will employ an array of powerful multidisciplinary techniques to modify specific components of mPFC circuitry testing two novel and independent hypothesis both directed at improving age-related cognitive dysfunction.