Alpha7 nicotonic receptor actions on GABAergic synapses

Nicotine derived from tobacco acts on receptors in the brain, which are normally activated by the endogenous neurotransmitter acetylcholine. Although nicotine abuse is an important cause of premature death and disease, activation of nicotinic receptors enhances cognitive performance. How it does so is not known. We have recently discovered a powerful effect of activation of a subtype of nicotinic receptors on inhibitory transmission in a subset of neurons in the brain. We propose to explore the underlying mechanisms, and to investigate the consequences of this phenomenon for network function.

Alpha7 nicotinic receptors enhance performance in cognitive tests, but their cellular roles are poorly understood. We have found that GABAergic transmission in hippocampal interneurons is profoundly down-regulated by agonists of alpha7 receptors. This action involves a change in GABAA receptors, rather than a presynaptic alteration in GABA release. Synaptically released ACh mimics the effect of exogenous agonists. This proposal focuses on the cell-type specificity of this phenomenon, its molecular mechanisms, and its consequences for network function. Understanding how ACh acts on cortical circuits will help to identify potential routes to mitigate the effects of degenerative disorders that affect cholinergic pathways, in particular Alzheimer s disease, and may also shed light on the mechanisms of nicotine addiction.