Dissection optique du rôle des récepteurs nicotiniques neuronaux à l'aide de récepteurs photo-contrôlables

Abstract

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels widely expressed in the central nervous system and the periphery. They play an important modulatory role in learning, memory and attention, and have been implicated in various diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, schizophrenia and addiction. These receptors are activated by the endogenous neurotransmitter acetylcholine, or by nicotine, the alkaloid found in tobacco leaves. Both molecules open the ion channel and cause the movement of cations across the membrane, which directly affects neuronal excitability and synaptic plasticity. nAChRs are very heterogeneous in their subunit composition (α2-10 et β2-4), in their brain distribution (cortex, midbrain, striatum…) and in their sub-cellular localization (pre- vs post-synaptic, axonal, dendritic…). This heterogeneity highly contributes to the very diverse roles these receptors have in health and disease. The ability to activate or block a specific nAChR subtype, at a defined time and space within the brain, would greatly help obtaining a clearer picture of these various functions. To this aim, we are developing novel optogenetic pharmacology strategies for optically controlling endogenous nAChR isoforms within the mouse brain. The idea is to tether a chemical photoswitch on the surface of a cysteine-modified nAChR, and use light for rapidly and reversibly turning that receptor mutant on and off. Here we will discuss the history of optogenetic pharmacology, and the recent advances for the optical control of brain nicotinic receptors in vivo.