Inhibitory Synaptic Plasticity

突触的可塑性被认为是学习和记忆的细胞基础。这一发现是数千名科学家50年来工作的顶峰，然而大多数工作都是在兴奋性谷氨酸能突触上进行的，尽管学习和记忆任务需要抑制。例如，灭活释放GABA的中间神经元可以防止情景恐惧条件反射，而消融海马区的中间神经元则可以阻止空间工作记忆。尽管抑制在神经网络功能中的重要性已经得到公认，而且抑制在学习和记忆中的作用也逐渐显现，但抑制性突触可塑性在学习和记忆中的作用尚不清楚。我的NSERC资助的研究项目的长期目标是了解大脑中抑制性突触的可塑性，无论是在神经元网络层面还是在行为层面。虽然我的实验室和我们的神经生理学同事已经在抑制性突触可塑性方面取得了深刻的发现--一个开创性的问题--但抑制性突触可塑性是学习的基础吗？这项拨款申请中提出的实验是回答这一问题所需的关键组成部分。为了确定抑制性突触可塑性在学习中的作用，我们将重点研究小鼠的初级运动皮质。在这个项目中，运动学习的主要优势包括运动学习是健壮的和可量化的，并且运动学习背后的神经回路已经被预先定义。目的1：研究大脑皮层抑制性突触可塑性。1.1一致的突触前和突触后放电是否诱导初级运动皮质的抑制性突触可塑性？1.2确定初级运动皮质的抑制性突触可塑性是否是神经元间特异性的。1.3以确定抑制性突触可塑性是否具有层和区域特异性。目的2：探讨皮层抑制突触可塑性的机制。2.1确定皮层抑制性突触可塑性诱导的机制(S)。2.2确定PKC介导的KCC2磷酸化是否在大脑皮层抑制突触可塑性中起基础作用。目的#3：确定抑制性突触可塑性和运动学习之间的联系。拟议的实验旨在描述大脑皮质中活性依赖的抑制性突触可塑性，包括确定潜在的机制、泛化水平及其在学习中的作用。这一原创性和创新性研究项目的结果将改变我们对大脑皮层抑制性突触可塑性的存在和作用以及学习机制的基本理解。

Synaptic plasticity is believed to be the cellular basis of learning and memory. This discovery is the culmination of 50 years of work by thousands of scientists, however most of this work has been performed on excitatory glutamatergic synapses, despite the requirement of inhibition for learning and memory tasks. For example, inactivating GABA-releasing interneurons prevents contextual fear conditioning, while ablation of interneurons in the hippocampus prevents spatial working memory. Despite the well accepted critical importance of inhibition in neural network function, and the emerging role of inhibition in learning and memory, the role of inhibitory synaptic plasticity in learning and memory is unknown. The long-term goal of my NSERC-funded research program is to understand inhibitory synaptic plasticity in the brain, both at the level of the neuronal network and in behaviour. While my lab, and those of our neurophysiology colleagues, have made profound discoveries regarding inhibitory synaptic plasticity - a seminal question remains - does inhibitory synaptic plasticity underlie learning? The experiments proposed in this grant application are a critical component required to answer this question. To determine the role of inhibitory synaptic plasticity in learning we will focus our experiments on the primary motor cortex of mice. The primary advantages of motor learning for this project include the fact that motor learning is robust and quantifiable, and that the neuronal circuitry underling motor learning has been previously defined. Objective #1: To characterize inhibitory synaptic plasticity in the cortex. 1.1 Does coincident pre-and postsynaptic spiking induce inhibitory synaptic plasticity in the primary motor cortex? 1.2 To determine whether inhibitory synaptic plasticity in the primary motor cortex is interneuron-specific. 1.3 To determine whether inhibitory synaptic plasticity is layer- and region-specific. Objective #2: To determine the mechanisms underlying cortical inhibitory synaptic plasticity. 2.1 To determine the mechanism(s) underlying the induction of inhibitory synaptic plasticity in the cortex. 2.2 To determine whether the PKC-mediated phosphorylation of KCC2 underlies inhibitory synaptic plasticity in the cortex. Objective #3: To determine a link between inhibitory synaptic plasticity and motor learning. The proposed experiments are designed to characterize activity-dependent inhibitory synaptic plasticity in the cortex, including determining the underlying mechanisms, level of generalizability, and its role in learning. Results from this original and innovative research program will alter our fundamental understanding of both the existence and role of inhibitory synaptic plasticity in the cortex, and the mechanisms underlying learning.