Frequency Dependence of Excitatory Synaptic Transmission

由抑制性中间神经元提供的抑制性突触传递对于以下两者都是必不可少的： 神经回路的功能和正常的大脑发育。余额 抑制性和兴奋性突触传递之间的联系对于神经元的正确连接至关重要。 大脑回路在出生后早期的发展。之间平衡的变化 抑制和兴奋已经在许多神经发育中被发现， 神经精神障碍，包括自闭症、唐氏综合征、脆性X综合征和 精神分裂症兴奋和抑制之间的平衡不是静态的，而是 在不同模式的刺激过程中通过短期可塑性动态变化。的 兴奋和抑制的强度都受到短期可塑性的调节， 这两种成分之间短期可塑性的差异导致了 从兴奋到抑制是频率依赖性的。在海马中，GABA能 中间神经元对兴奋性锥体细胞提供强有力的抑制， 预防癫痫和兴奋性中毒。此外，海马中间神经元可以 使锥体细胞的放电同步，并驱动 对学习和记忆至关重要。海马中间神经元在其功能上是高度多样的。 解剖学、神经化学和生理学特性。生理学知识 这些不同的中间神经元亚型的性质和功能作用，虽然需要 为了了解海马电路功能和行为之间的关系， 无论是正常还是疾病状态，都是有限的。在海马CA1区，前馈 抑制作用通过两条途径提供，即Schaffer侧支（SC）途径 辐射层（SR）中的中间神经元，以及颞氨（TA）通路， 腔隙分子层（SLM）的中间神经元。然而，人们对此知之甚少 前馈抑制的频率依赖性以及它如何影响 从兴奋到抑制在本提案中，我们将测试机制，功能效果， 以及前馈抑制的短期可塑性对电路功能的影响 从SC和TA途径转移到CA1锥体细胞上。这些数据将 提供的信息是必不可少的了解如何平衡的兴奋和 抑制是受管制的，短期可塑性如何帮助门的信息流，通过 海马，以及不同中间神经元亚型的正常功能作用。这 这些信息可以提供潜在的治疗靶点， 神经系统疾病，以及为未来的研究提供基础， 前馈抑制的短期可塑性在神经精神疾病中的作用 导致智力迟钝的神经发育障碍。

Inhibitory synaptic transmission provided by inhibitory interneurons is essential both for the functioning of neuronal circuits and for normal brain development. The balance between inhibitory and excitatory synaptic transmission is critical for the proper wiring of brain circuits during early postnatal development. Alterations in the balance between inhibition and excitation have been found in many neurodevelopmental and neuropsychiatric disorders, including autism, Down Syndrome, Fragile X Syndrome, and schizophrenia. The balance between excitation and inhibition is not static, but is dynamically changed during different patterns of stimulation by short-term plasticity. The strengths of both excitation and inhibition are modulated by short-term plasticity, and differences in short-term plasticity between these two components causes the balance of excitation to inhibition to be frequency-dependent. In hippocampus, GABAergic interneurons provide powerful inhibition to the excitatory pyramidal cells that is vital to prevent epilepsy and excitotoxicity. In addition, hippocampal interneurons can synchronize the firing of pyramidal cells and drive population oscillations that are essential for learning and memory. Hippocampal interneurons are highly diverse in their anatomical, neurochemical, and physiological properties. Knowledge of the physiological properties and functional roles of these different interneuron subtypes, although required for understanding the relationship between hippocampal circuit function and behavior in both normal and disease states, is still limited. In the CA1 region of hippocampus, feedforward inhibition is provided through two pathways, the Schaffer collateral (SC) pathway onto interneurons in stratum radiatum (SR), and the temporoammonic (TA) pathway onto interneurons in stratum lacunosum-moleculare (SLM). However, the little is known about the frequency-dependence of feed-forward inhibition and how it affects the balance of excitation to inhibition. In this proposal we will test the mechanisms, functional effects, and consequences for circuit function of short-term plasticity of feed-forward inhibition onto CA1 pyramidal cells from both the SC and TA pathways. Together these data will provide information that is essential to understanding how the balance of excitation and inhibition is regulated, how short-term plasticity helps gate the flow of information through hippocampus, and the normal functional roles of different interneuron subtypes. This information may provide potential therapeutic targets for selectively modifying inhibition in neurological disease, as well as providing a foundation for future studies investigating the role of short-term plasticity of feed-forward inhibition in neuropsychiatric disorders and neurodevelopmental disorders that cause mental retardation.