GABAergic Synaptic Transmission in the Aged Rat Brain

超出提供的空间。这项建议是对国家老龄研究所试点研究资助计划PAR-03-056，18-功能性衰老的回应。依赖于海马体的空间记忆能力减弱已经被很好地证明与人类和动物的衰老有关。越来越多的证据表明，这种认知能力的下降可能不是由于大量突触/神经元的丧失，而是由于突触功能和可塑性的损害。此外，谷氨酸和GABA能突触的可塑性与细胞内钙离子等多种机制和因素有关，GABA能突触传递的抑制可能在学习记忆形成中起积极作用。综上所述，我们假设与衰老相关的分子和细胞变化导致海马区GABA能突触的功能和可塑性受损，从而导致衰老相关的认知功能障碍。通过表征老年人大脑中的GABA能神经传递，我们将能够阐明其在衰老相关的学习和记忆形成障碍中的作用，并找到潜在的治疗干预靶点，以阻止正常衰老和疾病相关脑功能障碍的发生和发展。这项先导性研究的目的是积累与学习关键的海马区GABA能神经传递的衰老相关的重要数据。为了验证我们的假设和实现我们的目标，我们将实现以下具体目标：1)研究老年大鼠海马CA1区中间神经元和锥体细胞中GABA能突触的特性及其短期和长期调节。我们将采用包括双重记录、共聚焦荧光成像和免疫化学方法在内的综合方法，比较年轻和老年大鼠锥体细胞树突区和体体区以及中间神经元中的GABA能突触。2)确定与衰老相关的GABA能突触传递变化的功能后果。我们将确定GABA能突触如何与老年海马中的谷氨酸能通路相互作用，并比较空间学习障碍大鼠和正常老年大鼠GABA能神经传递的特性。表演网站========================================Section End===========================================

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===========================================