TY - JOUR T1 - Uropathic Observations in Mice Expressing a Constitutively Active Point Mutation in the 5-HT<sub>3A</sub> Receptor Subunit JF - The Journal of Neuroscience JO - J. Neurosci. SP - 5537 LP - 5548 DO - 10.1523/JNEUROSCI.5658-03.2004 VL - 24 IS - 24 AU - Anindya Bhattacharya AU - Hong Dang AU - Quan-Ming Zhu AU - Birthe Schnegelsberg AU - Nora Rozengurt AU - Gary Cain AU - Rachelle Prantil AU - David A. Vorp AU - Nicholas Guy AU - David Julius AU - Anthony P. D. W. Ford AU - Henry A. Lester AU - Debra A. Cockayne Y1 - 2004/06/16 UR - http://www.jneurosci.org/content/24/24/5537.abstract N2 - Mutant mice with a hypersensitive serotonin (5-HT)3A receptor were generated through targeted exon replacement. A valine to serine mutation (V13′S) in the channel-lining M2 domain of the 5-HT3A receptor subunit rendered the 5-HT3 receptor ∼70-fold more sensitive to serotonin and produced constitutive activity when combined with the 5-HT3B subunit. Mice homozygous for the mutant allele (5-HT3Avs/vs) had decreased levels of 5-HT3A mRNA. Measurements on sympathetic ganglion cells in these mice showed that whole-cell serotonin responses were reduced, and that the remaining 5-HT3 receptors were hypersensitive. Male 5-HT3Avs/vs mice died at 2-3 months of age, and heterozygous (5-HT3Avs/+) males and homozygous mutant females died at 4-6 months of age from an obstructive uropathy. Both male and female 5-HT3A mutant mice had urinary bladder mucosal and smooth muscle hyperplasia and hypertrophy, whereas male mutant mice had additional prostatic smooth muscle and urethral hyperplasia. 5-HT3A mutant mice had marked voiding dysfunction characterized by a loss of micturition contractions with overflow incontinence. Detrusor strips from 5-HT3Avs/vs mice failed to contract to neurogenic stimulation, despite overall normal responses to a cholinergic agonist, suggestive of altered neuronal signaling in mutant mouse bladders. Consistent with this hypothesis, decreased nerve fiber immunoreactivity was observed in the urinary bladders of 5-HT3Avs/vs compared with 5-HT3A wild-type (5-HT3A+/+) mice. These data suggest that persistent activation of the hypersensitive and constitutively active 5-HT3A receptor in vivo may lead to excitotoxic neuronal cell death and functional changes in the urinary bladder, resulting in bladder hyperdistension, urinary retention, and overflow incontinence. ER -