Optogenetics, an integrated strategy that uses light to control neuronal activity, has become a revolutionary technique for neuroscience investigations such as brain circuit mapping. However, this technique typically relies on exogenously introduced microbial opsins that do not participate in endogenous neuronal signaling. To gain mechanistic insights into neural functions, methods allowing optogenetic control over the native operators, especially neurotransmitter receptors that mediate synaptic transmission between neurons, are highly desirable. Here we combine synthetic chemistry and genetic engineering to enable optical control over GABAA receptors (GABAARs), the major mediators of inhibitory neurotransmission in the brain. We confer light sensitivity onto each GABAAR a-isoform by covalently conjugating a photo-switchable antagonist near the receptor's GABA-binding pocket. The installed antagonist isomerizes in response to two different wavelengths of light to turn off and restore the receptor activity. These light-regulated GABAARs can be employed in intact neural systems, enabling optical manipulation of inhibitory postsynaptic responses, synaptic plasticity, and in vivo cortical activities driven by visual stimulation. Our strategy thus expands the optogenetic toolkit and will facilitate the understanding of GABAAR-associated neural functions and disorders.

Engineering light-regulated GABA<sub>A</sub> receptors for optogenetic control of neural functions

248th National Meeting (2014)

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Engineering light-regulated GABAA receptors for optogenetic control of neural functions

Engineering light-regulated GABA_A receptors for optogenetic control of neural functions