Inhibitory Synaptic Plasticity

突触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年工作的成果，然而，尽管学习和记忆任务需要抑制，但大多数工作都是在兴奋性突触上进行的。例如，失活释放GABA的中间神经元阻止了情境恐惧条件反射，而海马体中的中间神经元的消融阻止了空间工作记忆。尽管抑制在神经网络功能中的重要性已被广泛接受，并且抑制在学习和记忆中的作用正在显现，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资助的研究计划的长期目标是了解大脑中的抑制性突触可塑性，无论是在神经元网络的水平和行为。 虽然我的实验室和我们的神经生理学同事在抑制性突触可塑性方面取得了深刻的发现--但一个开创性的问题仍然存在--抑制性突触可塑性是学习的基础吗？在这项资助申请中提出的实验是回答这个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，我们将把实验重点放在小鼠的初级运动皮层上。运动学习对于这个项目的主要优势包括运动学习是稳健的和可量化的，并且运动学习的神经元回路先前已经被定义。 目标#1：表征皮层中抑制性突触可塑性。1.1突触前和突触后同步发放是否诱导初级运动皮层的抑制性突触可塑性？ 1.2确定初级运动皮层中抑制性突触可塑性是否是神经元间特异性的。1.3确定抑制性突触可塑性是否具有层特异性和区域特异性。目的#2：确定皮层抑制性突触可塑性的机制。2.1确定皮层中抑制性突触可塑性诱导的潜在机制。 2.2确定PKC介导的KCC 2磷酸化是否是皮质中抑制性突触可塑性的基础。目标3：确定抑制性突触可塑性和运动学习之间的联系。所提出的实验旨在表征皮层中的活动依赖性抑制性突触可塑性，包括确定潜在的机制，概括性水平及其在学习中的作用。这项原创性和创新性研究计划的结果将改变我们对皮层中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.