Histamine Regulation of Basal Ganglia Function

摘要 基底节回路--包括初级输入核、纹状体--关键地调节 许多行为过程，并与多种神经精神疾病的病理生理学有关 条件，包括抽动症(TS)和强迫症(OCD)。对 基底节中的调节性神经递质多巴胺(DA)已被广泛研究。更少的是 已知组胺(HA)对这一回路的调节。最近的发现突显了 基底神经节HA调节失调在神经精神疾病中的作用，尤其是TS和 强迫症。组氨酸脱羧酶(HDC)的突变，HDC是生产HA所需的关键生物合成酶， 被确认为TS的罕见原因，外显率较低的强迫症。我们对HDC基因敲除小鼠的研究 证实HA破坏可导致TS相关行为和纹状体神经化学和 功能。来自小鼠模型的初步数据将注意力集中在组胺受体H3R上，它是 在纹状体中高度表达。 H3R在基底节发出的信号还不是很清楚。最近的研究，其中大部分是体外研究，已经 已有文献证明H3R与D1R和D2R多巴胺受体之间的异源二聚作用，并表明 H3R和D1R在MAPK的调节中以违反直觉的方式相互作用。G-的这种异二聚化 蛋白质偶联受体的报道越来越多，但其功能意义一直难以确定。 我们在体内复制了H3R-D1R功能相互作用，并确定了行为相关性。我们有 还发现了H3R通过AKT-GSK3β对信号的一种新的细胞类型特异性作用：在纹状体介质中 表达D1R(D1R-MSN)、H3R的带刺神经元导致Gsk3β的磷酸化(从而失活)， 而在D2R-MSNS中，它导致GSK3β去磷酸化。这种对MAPK和MAPK的不同调控 Gsk3β强调了H3R-DR功能相互作用调节信号的能力以及 更好地理解纹状体调节的这一维度。 我们建议使用现有的转基因小鼠品系来表征H3R之间的功能相互作用 背侧纹状体D1R-和D2R-MSN的多巴胺受体。我们预测非线性相互作用在 MAPK和GSK3β的调节，这将导致运动调节中的相互作用 活动。我们将通过产生可诱导的H3R来测试H3Rs在特定纹状体细胞类型中的因果重要性 基因敲除小鼠，我们将其与表达细胞类型特异性cre的转基因小鼠杂交，产生D1R-和 D2R-MSN特有的H3R信号中断。我们预测了信号和信号水平上的差异效应 H3R在不同MSN亚型中中断时的行为。这些实验将为我们提供新的线索 透明质酸在基底节功能调节中的作用被低估，并为未来奠定基础 病理生理学动物模型的研究。

ABSTRACT The basal ganglia circuitry – including the primary input nucleus, the striatum – critically regulates numerous behavioral processes and is implicated in the pathophysiology of multiple neuropsychiatric conditions, including Tourette syndrome (TS) and obsessive-compulsive disorder (OCD). Regulation of the basal ganglia by the modulatory neurotransmitter dopamine (DA) has been extensively studied. Much less is known about the regulation of this circuitry by histamine (HA). Recent findings have highlighted the contribution of dysregulated HA modulation of the basal ganglia to neuropsychiatric disease, especially TS and OCD. A mutation in histidine decarboxylase (Hdc), the key biosynthetic enzyme required for HA production, was identified as a rare cause of TS and, with lower penetrance, of OCD. Our studies in Hdc knockout mice confirm that HA disruption can lead to TS-relevant behaviors and changes in striatal neurochemistry and function. Preliminary data from the mouse model focus attention on the histamine receptor H3R, which is highly expressed in the striatum. Signaling by H3R in the basal ganglia is not well understood. Recent work, most of it ex vivo, has documented heterodimerization between H3R and both D1R and D2R dopamine receptors and shown that H3R and D1R interact in counterintuitive ways in the regulation of MAPK. Such heterodimerization of G- protein-coupled receptors is increasingly reported, but its functional significance has been difficult to pin down. We have replicated H3R-D1R functional interactions in vivo and identified a behavioral correlate. We have also identified a novel, cell-type specific effect of H3R on signaling through AKT-GSK3β: in striatal medium spiny neurons that express D1R (D1R-MSNs), H3R leads to phosphorylation (and thus inactivation) of GSK3β, while in D2R-MSNs it leads to GSK3β dephosphorylation. This differential regulation of both MAPK and GSK3β highlights the ability of H3R-DR functional interactions to modulate signaling and the importance of better understanding this dimension of striatal regulation. We propose to use existing transgenic mouse lines to characterize functional interactions between H3R and dopamine receptors in D1R- and D2R-MSNs of the dorsal striatum. We predict nonlinear interactions in the regulation of both MAPK and GSK3β, and that these will lead to interactions in the regulation of locomotor activity. We will test the causal importance of H3Rs in specific striatal cell types by generating inducible H3R knockout mice, which we will cross with cell type-specific cre-expressing transgenic mice to produce D1R- and D2R-MSN-specific disruption of H3R signaling. We predict differential effects at the level of both signaling and behavior when H3R is disrupted in different MSN subtypes. These experiments will shed new light on the underappreciated role of HA in the modulation of basal ganglia function and lay the groundwork for future studies in animal models of pathophysiology.