Megacystis, mydriasis, and ion channel defect in mice lacking the alpha3 neuronal nicotinic acetylcholine receptor.

[megacystis-microcolon-intestinal hypoperistalsis syndrome]

The alpha 3 subunit of the neuronal nicotinic acetylcholine receptor is widely expressed in autonomic ganglia and in some parts of the brain . The alpha 3 subunit can form heteromultimeric ion channels with other alpha subunits and with beta 2 and beta 4 subunits , but its function in vivo is poorly understood . We prepared a null mutation for the alpha 3 gene by deletion of exon 5 and found that homozygous (-/-) mice lacked detectable mRNA on Northern blotting . The -/- mice survive to birth but have impaired growth and increased mortality before and after weaning . The -/- mice have extreme bladder enlargement , dribbling urination , bladder infection , urinary stones , and widely dilated ocular pupils that do not contract in response to light . Detailed histological studies of -/- mice revealed no significant abnormalities in brain or peripheral tissues except urinary bladder , where inflammation was prominent . Ganglion cells and axons were present in bladder and bowel . Bladder strips from -/- mice failed to contract in response to 0 .1 mM nicotine , but did contract in response to electrical field stimulation or carbamoylcholine . The number of acetylcholine-activated single -channel currents was severely reduced in the neurons of superior cervical ganglia in -/- mice with five physiologically distinguishable nicotinic acetylcholine receptor subtypes with different conductance and kinetic properties in wild-type 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 nicotinic receptors mediating normal function of the autonomic nervous system . The phenotype in -/- mice may be similar to the rare human genetic disorder of megacystis-microcolon -intestinal hypoperistalsis syndrome .