Neuronal nicotinic receptors: insights gained from gene knockout and knockin mutant mice

Neuronal nicotinic acetylcholine receptors are ligand-gated ion channels that subserve a range of functions in the brain and peripheral nervous system. They are pentamers variously composed of alpha (alpha2-alpha10) and beta subunits (beta2-beta4). Pharmacological and ligand-binding studies have shown that the different subunits vary in their distribution and channel properties, but precise delineation of the in vivo function of individual subunits has been hampered by lack of subunit-specific antagonists. The development of transgenic mice with targeted deletions of specific subunits (knockout mice) or mutations in critical receptor domains (knockin mice) has extended understanding of nicotinic receptors, revealing that some subunits are necessary for viability, whereas others mediate modulatory effects on learning and memory, locomotion, anxiety, nociception, dopaminergic neurotransmission, seizure threshold, development of the visual system and autonomic function. In some cases, studies of transgenic mice have confirmed expectations derived from pharmacological and expression studies, but in other cases, compensation by related subunits has revealed a degree of functional redundancy not predicted by previous approaches.