GABA and glutamate are the main inhibitory and excitatory neurotransmitters in the brain. Activity-dependent redistribution of glutamate receptors contributes to excitatory long-term synaptic plasticity, learning and memory. A similar redistribution of GABAA receptors (GABAARs) has been shown to occur in neuronal culture, but the functional significance of this process in intact brain circuits remains unclear. Our goal is to better understand the role that GABAA receptors play in synaptic plasticity in the hippocampus, a brain region crucial for learning and memory. We have developed photoswitch chemicals that allow light to reversibly block GABAA receptors with high spatial and temporal precision and absolute specificity for a specified mutant ?-subunit. Here we focus on receptors containing either the broadly- expressed ?1-subunit, or the hippocampus-enriched ?5-subunit. To enable photo-control of endogenous receptors, we have developed knock-in mice with photoswitch-ready version of ?1 or ?5 replacing their wild-type counterparts. Using these mice and novel intrabody probes that light-up or disrupt GABAARs scaffolds, we will evaluate where ?1- and ?5-GABAARs are in neurons, how they contribute to synaptic function, and what role they play in synaptic plasticity.
Aim 1 is to map the distribution of the two GABAA types in hippocampal neurons. This includes determining whether they are expressed in proximal to distal dendritic gradients, determining whether they are aggregated at synapses or dispersed extrasynapatically, and determining their individual contributions to inhibitory synaptic transmission from different identified inhibitory interneurons.
Aim 2 is to investigate how neuronal activity alters the distribution of GABAARs. This includes using the photoswitch as a stable tag to evaluate whether activity alters the lifespan and lateral mobility of the receptors on the plasma membrane.
Aim 3 is to investigate how GABAARs alter excitatory long-term synaptic plasticity. This includes investigating the impact of the GABAARs on induction of long-term potentiation and depression and NMDA receptor signaling. The knowledge gained from this work will fill a gaping hole in our understanding of brain function and may reveal new treatment strategies for memory disorders and other neurological diseases. !
The neurotransmitter GABA acts on receptors in brain cells to inhibit their activity. GABA receptors are associated with many disorders, including insomnia, anxiety, alcoholism, Alzheimer's disease, chronic pain, schizophrenia, bipolar affective disorders, and epilepsy. Our goal is to better understand the role that GABA receptors play in a region of the brain that is crucial for learning and memory, with the hope of revealing new treatment strategies for memory disorders and other neurological diseases.
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