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

描述（由申请人提供）：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久性行为的神经机制。感觉运动门控是一种过滤过多感觉、认知和运动信息的神经机制，允许精神和行为整合。预脉冲抑制（PPI）是惊吓可塑性的一种形式，为感觉运动门控提供了一种操作措施。最近的研究发现，在两种以PPI缺陷和持续行为为特征的疾病：强迫症（OCD）和自闭症中，5- httt的功能获得性突变和5-HT1DP（同源于小鼠5-HT1B）受体的超敏反应。只有有效阻断血清素再吸收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研究发现，5- httt和5-HT1B受体之间在调节PPI和持久性行为方面存在功能相互作用。我们发现5-HT1B基因敲除小鼠不存在急性5-HT1B激动剂刺激引起的PPI缺陷和持久性行为。我们还发现，用选择性血清素再摄取抑制剂氟西汀慢性治疗的小鼠不存在5-HT1B激动剂诱导的行为缺陷，但亚慢性治疗的小鼠不存在。因此，我们假设降低5-HT1B受体的基因或药理学功能，可以通过使这些受体脱敏来防止5-HT1B受体激活引起的PPI缺陷和持久性行为。我们还假设，基因或药理学上，5- httt功能的增加会加剧5-HT1B受体激活引起的行为缺陷，使这些受体变得敏感。在这里，我们建议确定5-HTT和5-HT1B受体相互作用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，来验证需要有效阻断5-HTT来预防5-HT1B激动剂诱导的行为缺陷的假设。其次，我们将评估5-HT1B受体的表达和功能偶联，以定位抗抑郁药物治疗导致5-HT1B受体脱敏的大脑区域。第三，我们将产生两个具有增加5-HTT功能的诱导转基因小鼠品系。一种菌株将过度表达小鼠5-HTT来评估增加5-HTT可用性的影响，这可能模拟最近与强迫症相关的特定5-HTT基因连锁多态性区域（5-HTTLPR）等位基因的后果。另一种菌株将表达人类5-HTT，其中包含一种罕见的突变Ne425Val，该突变使5-HTT具有组成性活性，最近与强迫症和自闭症有关。我们假设这两种小鼠品系都会表现出PPI缺陷和持久性行为，以及对5-HT1B激动剂的行为反应增加。我们独特的方法可能会导致强迫症和自闭症中感觉运动门控缺陷和持续行为的新动物模型。

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.