Role of neuronal nitric oxide in neuroplasticity-associated gene expression

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DESCRIPTION (provided by applicant): Role of neuronal nitric oxide in neuroplasticity-associated gene expression A fundamental feature of the mammalian brain is its ability to undergo long-lasting modifications in response to alterations in neural activity. This neuroplasticity occurs from early development into adulthood, and is essential for normal cognitive function, including learning and memory. Aging and aging-related brain disorders such as Alzheimer's disease are characterized by a loss of cognition, a phenomenon linked to a profound impairment of synaptic plasticity. Therefore, gaining an understanding of the mechanisms underlying synaptic plasticity may provide insight into new approaches to ameliorate the cognitive dysfunction associated with normal and abnormal brain aging. The NMDA-type glutamate receptor (NMDAR) plays a central role in synaptic plasticity, yet the factors and mechanisms which regulate its downstream signaling are not fully understood. Production of nitric oxide (NO) by the neuronal isoform of nitric oxide synthase (nNOS) has emerged as a key player in NMDAR signaling. In addition, NMDAR-dependent NO production plays an important role in various forms of neuroplasticity. However, it is unclear how this short-lived molecule results in the long-term functional modifications that characterize neuroplasticity. The central hypothesis set forth in this proposal is that NO produced during activation of NMDAR plays a role in the expression of genes encoding key proteins required for synaptic plasticity, such as the transcription factors c-Fos and Egr-1, and the synaptic effector proteins BDNF and Arc. The first aim will test the hypothesis that nNOS-derived NO contributes to neuroplasticity-associated gene expression. The second aim will test the hypothesis that the effects of nNOS-derived NO on gene expression are mediated by ERK signaling. To achieve these goals, we will use well-established models of neuroplasticity in the mouse whisker barrel cortex and in primary neuronal cultures. The role of NO will be studied using pharmacological inhibitors or nNOS-deficient mice. PUBLIC HEALTH RELEVANCE: Cognitive dysfunction in aging and related diseases, such as Alzheimer's disease, is a major problem with a rapidly expanding public health impact due to the increasing age of the general population. The proposed studies will enhance our understanding of the cellular mechanisms underlying neuroplasticity, a property of synapses that is essential for normal cognition. The new information derived from these studies may provide the bases for novel preventive and treatment strategies for cognitive loss in normal and abnormal aging.