GABAergic Synaptic Transmission in the Aged Rat Brain

超出所提供的空间。 该提案是对国家老龄化研究所试点研究资助计划PAR-03- 056，18-功能性衰老的回应。已经有大量文献证明，人类和动物的大脑依赖性空间记忆能力下降与衰老有关。越来越多的证据表明，这种认知能力下降可能不是由于大量突触/神经元的损失，而是由于突触功能和可塑性受损。此外，多巴胺能和GABA能突触的可塑性已被证明有许多共同的机制和因素，如细胞内Ca 2+，抑制性GABA能突触传递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中GABA能突触的功能和可塑性受损，从而导致与衰老相关的认知障碍。通过表征老年大脑中的GABA能神经传递，我们将能够阐明其在与衰老相关的学习和记忆形成障碍中的作用，并找到可能阻止正常衰老和疾病相关脑功能障碍的发生和发展的治疗干预的潜在靶点。本研究的目的是为学习关键海马区GABA能神经传递的增龄性变化积累有意义的数据。为了验证我们的假设并实现我们的目标，我们将进行以下具体的目的：1）表征老年大鼠海马CA 1区中间神经元和锥体细胞中GABA能突触的性质和短、长时程调制。GABA能突触的树突状细胞和体细胞区域的锥体细胞和中间神经元之间的比较年轻和老年大鼠的综合方法，包括双记录，共聚焦荧光成像和免疫化学方法。2)确定GABA能突触传递中衰老相关变化的功能后果。我们将确定GABA能突触如何与老年海马中的突触能通路相互作用，并比较空间学习受损和未受损老年大鼠之间GABA能神经传递的性质。性能现场=

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