Tuesday, April 1, 2025
4/1/2025
The role of subsynaptic nanoscale architecture in inhibitory synaptic plasticity - PROJECT SUMMARY Synaptic inhibition in the brain is critical for controlling neuronal circuit function, and its disruption underlies the pathology of multiple neurological, psychiatric, and neurodevelopment disorders including epilepsy, anxiety, autism, and schizophrenia. GABAergic inhibitory synapses mediate synaptic inhibition and regulate neuronal excitability, cell firing, dendritic integration, and synaptic plasticity. Synaptic plasticity mechanisms drive changes in synaptic strength in response to increased or decreased neuronal activity, which results in long-term alterations responsible for learning, memory, and cognition. In one form of inhibitory synaptic plasticity, inhibitory long-term potentiation (iLTP), GABAA receptors (GABAARs) accumulate at inhibitory synapses and are stabilized, consequently increasing synaptic strength. However, the precise organization of newly recruited synaptic GABAARs during iLTP and how this may contribute to increased synaptic strength is unknown. Advances in super-resolution (SR) imaging techniques have revealed a common nanoscale architecture at synapses in which neurotransmitter receptors, scaffolds, and adhesion molecules cluster into subsynaptic domains (SSDs). Under basal conditions, SSDs of GABAARs require positioning close to sites of presynaptic release for efficient synaptic transmission. This structured architecture is defined as the inhibitory nanocolumn. It remains unclear if newly recruited GABAARs organize into SSDs within nanocolumns during iLTP, and whether alterations to the inhibitory nanocolumn are required for synaptic potentiation. The overall goal of this proposal is to determine how inhibitory synaptic nanostructure contributes to iLTP, and if the inhibitory synaptic nanocolumn is a locus for synaptic plasticity. I hypothesize that precise positioning of GABAARs into SSDs within the inhibitory nanocolumn opposite presynaptic release sites is an important mechanism involved in functional iLTP. Using a range of super-resolution microscopy techniques, optogenetics, and electrophysiology I will: identify changes in the size and density of GABAAR SSDs during iLTP, and importantly their positioning within the inhibitory nanocolumn (Aim 1), determine whether mobile GABAARs are trapped in nanoscale SSDs during iLTP (Aim 2), and investigate if positioning of GABAARs within the inhibitory nanocolumn is required for synaptic potentiation (Aim 3). Together, this approach will determine a detailed understanding of the precise nanoscale organization of GABAARs at inhibitory synapses during iLTP and provide crucial insight into key mechanisms involved in inhibitory plasticity, overall synapse function, and neuronal activity.
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