Megacystis, mydriasis, and ion channel defect in mice lacking the alpha 3 neuronal nicotinic acetylcholine receptor

The alpha 3 subunit of the neuronal nicotinic acetylcholine receptor is wid ely expressed in autonomic ganglia and in some parts of the brain, The alph a 3 subunit can form heteromultimeric ion channels with other alpha subunit s and with beta 2 and beta 4 subunits, but its function in vivo is poorly u nderstood. We prepared a null mutation for the alpha 3 gene by deletion of exon 5 and found that homozygous (-/-) mice lacked detectable mRNA on North ern blotting, The -/- mice survive to birth but have impaired growth and in creased mortality before and after weaning, The -/- mice have extreme bladd er enlargement, dribbling urination, bladder infection, urinary stones, and widely dilated ocular pupils that do not contract in response to light, De tailed histological studies of -/- mice revealed no significant abnormaliti es in brain or peripheral tissues except urinary bladder, where inflammatio n was prominent. Ganglion cells and axons were present in bladder and bowel , Bladder strips from -/- mice failed to contract in response to 0.1 mPrl n icotine, but did contract in response to electrical field stimulation or ca rbamoylcholine, The number of acetylcholine-activated single-channel curren ts was severely reduced in the neurons of superior cervical ganglia in -/- mice with five physiologically distinguishable nicotinic acetylcholine rece ptor subtypes with different conductance and kinetic properties in wild-typ e mice, all of which were reduced in -/- mice. The findings in the alpha 3- null mice suggest that this subunit is an essential component of the nicoti nic receptors mediating normal function of the autonomic nervous system. Th e phenotype in -/- mice may be similar to the rare human genetic disorder o f megacystis-microcolon-intestinal hypoperistalsis syndrome.