We propose to use behavioral and genetic mouse models to identify the neural mechanisms by which serotonin transporter (5-HTT) function modulates sensorimotor gating deficits and perseverative behaviors. Sensorimotor gating is a neural mechanism that filters excessive sensory, cognitive, and motor information, permitting mental and behavioral integration. Prepulse inhibition (PPI) is a form of startle plasticity that provides an operational measure of sensorimotor gating. Recent findings have implicated gain-of-function mutations in 5-HTT, and hypersensitivity of 5-HT1DP (homologous to mouse 5-HT1B) receptors, in two disorders characterized by deficient PPI and perseverative behaviors: obsessive-compulsive disorder (OCD) and autistic disorders. Only antidepressant drugs that potently block the reuptake of serotonin provide effective treatment for these disorders. Our recent findings in mice have identified a functional interaction between 5-HTT and 5-HT1B receptors in modulating PPI and perseverative behaviors. We found that the PPI deficits and perseverative behaviors induced by acute 5-HT1B agonist challenge are absent in 5-HTT knockout mice. We also found that the behavioral deficits induced by 5-HT1B agonists are absent in mice treated chronically, but not subchronically, with the selective serotonin reuptake inhibitor fluoxetine. Thus, we hypothesize that reducing 5-HTT function, genetically or pharmacologically, prevents the PPI deficits and perseverative behaviors induced by 5-HT1B receptor activation by desensitizing these receptors. We also hypothesize that increasing 5-HTT function, genetically or pharmacologically, will exacerbate the behavioral deficits induced by 5-HT1B receptor activation by sensitizing these receptors. Here, we propose to identify the mechanisms by which 5-HTT and 5-HT1B receptors interact to modulate these behaviors. First, we will test the hypothesis that potent blockade of 5-HTT is required to prevent 5-HT1B agonist-induced behavioral deficits by comparing the ability of different classes of antidepressants to reverse these effects. Second, we will assess 5-HT1B receptor expression and functional coupling to localize the brain regions in which 5-HT1B receptors are desensitized by antidepressant treatments. Third, we will generate two inducible transgenic mouse strains with increased 5-HTT function. One strain will overexpress mouse 5-HTT to evaluate the effects of increased 5-HTT availability, which may model the consequences of specific 5-HTT gene-linked polymorphic region (5-HTTLPR) alleles recently linked to OCD. The other strain will express human 5-HTT containing an uncommon mutation, Ne425Val, which renders 5-HTT constitutively active and was recently linked to OCD and autism. We hypothesize that both mouse strains will exhibit PPI deficits and perseverative behaviors, and increased behavioral responses to 5-HT1B agonists. Our unique approach could lead to novel animal models of the sensorimotor gating deficits and perseverative behaviors in OCD and autism. ? ? ?
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