Inhibitory Synaptic Plasticity

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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.