Multiorgan Autonomic Dysfunction in Mice Lacking the beta 2 and the beta 4 Subunits of Neuronal Nicotinic Acetylcholine Receptors

Transcripts for the beta 2 and the beta 4 nicotinic acetylcholine receptor (nAChR) subunits are found throughout the CNS and the peripheral nervous system. These two beta subunits can form heteromultimeric channels with any of the alpha 2, alpha 3, alpha 4, or alpha 5 subunits in heterologous expression systems. Nonetheless, the subunit composition of native nAChRs and the role of different nAChR subtypes in vivo remain unclear. We prepared null mutations for the beta 2 and the beta 4 genes and bred beta 2-/- beta 4-/- mice by mating mice of identical beta 2-/- beta 4+/- or beta 2+/- beta 4- /- genotype. The beta 2-/- and the beta 4-/- single-mutant mice grow to adulthood with no visible phenotypic abnormalities. The beta 2-/- beta 4-/- double mutants survive to birth but have impaired growth and increased perinatal mortality. They also present enlarged bladders with dribbling urination and develop urinary infection and bladder stones. The ocular pupils are widely dilated and do not constrict in response to light. Histological studies revealed no significant abnormalities of brain or peripheral tissues except for hyperplasia in the bladder mucosa of beta 4-/- and beta 2-/- beta 4-/- mutants. Bladder strips from beta 2-/- beta 4-/- mice did not respond to nicotine but contracted when stimulated with a muscarinic agonist or electric field stimulation. Bladder strips from beta 4 mutants did not respond to nicotine despite the absence of major bladder dysfunction in vivo. Acetylcholine-activated whole-cell currents were absent in superior cervical ganglion neurons from beta 2-/- beta 4-/- mice and reduced in neurons from beta 4-/- mice. Although there is apparent redundancy and a superficially normal phenotype in beta 2-/- and beta 4-/- mice, physiological studies indicate major deficits in the beta 4-/- mice. Our previous description of a similar phenotype in alpha 3-/- mice and the current data suggest that the alpha 3 and the beta 4 subunits are major components in autonomic nAChRs. The phenotype of the beta 2-/- beta 4-/- and alpha 3-/- mice resembles the autosomal recessive megacystis-microcolon-hypoperistalsis syndrome in humans.