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The Journal of Neuroscience, November 1, 1999, 19(21):9298-9305

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

Wei Xu¹, Avi Orr-Urtreger⁶, Filippo Nigro³, Shari Gelber⁴, Cara Ballard Sutcliffe¹, Dawna Armstrong², James W. Patrick³, Lorna W. Role^{4, 5}, Arthur L. Beaudet¹, and Mariella De Biasi³

Departments of ¹ Molecular and Human Genetics and ² Pathology and ³ Division of Neuroscience, Baylor College of Medicine, Houston, Texas, 77030, ⁴ Center for Neurobiology and Behavior and ⁵ Department of Anatomy and Cell Biology, Columbia University, New York, New York, 10032, and ⁶ The Genetics Institute, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel

Transcripts for the 2 and the 4 nicotinic acetylcholine receptor (nAChR) subunits are found throughout the CNS and the peripheral nervous system. These two  subunits can form heteromultimeric channels with any of the 2, 3, 4, or 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 2 and the 4 genes and bred 2/4/ mice by mating mice of identical 2/4+/ or 2+/4/ genotype. The 2/ and the 4/ single-mutant mice grow to adulthood with no visible phenotypic abnormalities. The 2/4/ 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 4/ and 2/4/ mutants. Bladder strips from 2/4/ mice did not respond to nicotine but contracted when stimulated with a muscarinic agonist or electric field stimulation. Bladder strips from 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 2/4/ mice and reduced in neurons from 4/ mice. Although there is apparent redundancy and a superficially normal phenotype in 2/ and 4/ mice, physiological studies indicate major deficits in the 4/ mice. Our previous description of a similar phenotype in 3/ mice and the current data suggest that the 3 and the 4 subunits are major components in autonomic nAChRs. The phenotype of the 2/4/ and 3/ mice resembles the autosomal recessive megacystis-microcolon-hypoperistalsis syndrome in humans.

Key words: neuronal nicotinic  subunits; autonomic ganglia; autonomic dysfunction; knock-out mice; bladder; eye

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19219298-08$05.00/0

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