Mechanisms for 5-HTT control of PPI and perseverative behavior using mouse models

描述(申请人提供)：我们建议使用行为和遗传小鼠模型来确定5-羟色胺转运体(5-HTT)功能调节感觉运动、门控缺陷和持之以恒行为的神经机制。感觉运动门控是一种神经机制，它过滤过多的感觉、认知和运动信息，允许精神和行为的整合。预脉冲抑制(PPI)是惊恐可塑性的一种形式，它提供了一种感觉运动门控的操作措施。最近的发现表明，5-HTT的功能获得突变和5-HT1DP(与小鼠的5-HT1B同源)受体的超敏反应，与两种以PPI缺陷和持久性行为为特征的疾病有关：强迫症(OCD)和自闭症。只有能有效阻止5-羟色胺再摄取的抗抑郁药物才能有效治疗这些疾病。我们最近在小鼠身上的发现证实了5-HTT和5-HT1B受体之间在调节PPI和持久力行为方面的功能相互作用。我们发现，在5-HTT基因敲除小鼠中，不存在由急性5-HT1B激动剂激发引起的PPI缺陷和持久行为。我们还发现，在长期使用选择性5-羟色胺再摄取抑制剂氟西汀治疗的小鼠中，5-HT1B激动剂引起的行为缺陷是不存在的，但不是亚慢性治疗。因此，我们假设，降低5-HTT的功能，从基因或药物上，通过脱敏5-HT1B受体来防止PPI缺陷和5-HT1B受体激活引起的持久性行为。我们还假设，增加5-HTT的功能，从遗传学或药理学上，将加剧由5-HT1B受体激活引起的行为缺陷，通过敏化这些受体。在这里，我们建议确定5-HTT和5-HT1B受体相互作用来调节这些行为的机制。首先，我们将通过比较不同类别的抗抑郁药逆转5-HT1B激动剂诱导的行为缺陷的能力来检验这一假设，即需要有效地阻断5-HTT来防止5-HT1B激动剂诱导的行为缺陷。其次，我们将评估5-HT1B受体的表达和功能耦合，以定位5-HT1B受体被抗抑郁药物治疗脱敏的脑区。第三，我们将产生两个可诱导的5-HTT功能增强的转基因小鼠品系。一个品系将过度表达小鼠5-HTT，以评估5-HTT可用性增加的影响，这可能会模拟最近与强迫症有关的特定5-HTT基因连锁多态区域(5-HTTLPR)等位基因的后果。另一株将表达含有不常见突变Ne425Val的人类5-HTT，该突变使5-HTT具有结构性活性，最近被认为与强迫症和自闭症有关。我们假设，两个品系的小鼠都将表现出PPI缺陷和持久力行为，并对5-HT1B激动剂的行为反应增加。我们独特的方法可能导致强迫症和自闭症感觉运动门控缺陷和持之以恒行为的新动物模型。

DESCRIPTION (provided by applicant): 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.