EXCEED THE SPACE PROVIDED. This proposal is in response to the National Institute on Aging Pilot Research Grant Program PAR-03- 056, 18-Functional Senescence. Diminished hippocampus-dependent spatial memory capacity has been well documented to be associated with aging in humans and animals. Increasing evidence indicates that this cognitive decline may not be due to a loss of significant numbers of synapses/neurons but rather due to compromised synaptic function and plasticity. Furthermore, the plasticity of glutamatergic and GABAergic synapses has been shown to share many mechanisms and factors such as intracellular Ca 2., and the inhibitory GABAergic synaptic transmission may play an active role in learning and memory formation. Taken together, we hypothesize that aging-related molecular and cellular changes lead to compromised function and plasticity of GABAergic synapses in the hippocampus, which contribute to aging-associated cognitive impairment. By characterizing the GABAergic neurotransmission in the aged brain, we will be able to elucidate its role in aging-related impairments of learning and memory formation and find potential targets for therapeutic interventions that could impede the onset and development of normal aging and disease- related brain dysfunctions. The objective of this pilot research is to accumulate significant data on aging- related changes of GABAergic neurotransmission in the learning-critical hippocampus. To test our hypothesis and accomplish our objectives, we will carry out the following Specific Aims: 1) To characterize the properties and short- and long-term modulations of GABAergic synapses in aged rat hippocampal CA1 interneurons and pyramidal cells. GABAergic synapses in the dendritic and somatic regions of pyramidal cells and in interneurons will be compared between young and aged rats with an integrated approach that includes dual-recordings, confocal fluorescence imaging and immunochemical methods. 2) To determine the functional consequences of aging-related changes in GABAergic synaptic transmission. We will determine how GABAergic synapses interact with glutamatergic pathways in the aged hippocampus, and compare the properties of GABAergic neurotransmission between spatial learning-impaired and -intact aged rats. PERFORMANCE SITE ========================================Section End===========================================
