Multiorgan autonomic dysfunction in mice lacking the beta 2 and the beta 4subunits 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 sy stem. These two beta subunits can form heteromultimeric channels with any o f the alpha 2, alpha 3, alpha 4, or alpha 5 subunits in heterologous expres sion 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-/- m ice by mating mice of identical beta 2-/-beta 4+/- or beta 2+/-beta 4-/- ge notype. The beta 2-/- and the beta 4-/- single-mutant mice grow to adulthoo d with no visible phenotypic abnormalities. The beta 2-/-beta 4-/- double m utants survive to birth but have impaired growth and increased perinatal mo rtality. They also present enlarged bladders with dribbling urination and d evelop urinary infection and bladder stones. The ocular pupils are widely d ilated and do not constrict in response to light. Histological studies reve aled no significant abnormalities of brain or peripheral tissues except for hyperplasia in the bladder mucosa of beta 4-/- and beta 2-/-beta 4-/- muta nts. Bladder strips from beta 2-/-beta 4-/- mice did not respond to nicotin e but contracted when stimulated with a muscarinic agonist or electric fiel d stimulation. Bladder strips from b4 mutants did not respond to nicotine d espite the absence of major bladder dysfunction in vivo. Acetylcholine-acti vated whole-cell currents were absent in superior cervical ganglion neurons from beta 2-/-beta 4-/- mice and reduced in neurons from beta 4-/- mice. A lthough there is apparent redundancy and a superficially normal phenotype i n beta 2-/- and beta 4-/- mice, physiological studies indicate major defici ts in the beta 4-/- mice. Our previous description of a similar phenotype i n alpha 3-/- mice and the current data suggest that the a3 and the b4 subun its 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.