Modulation of the autonomic nervous system and behaviour by acute glial cell Gq protein-coupled receptor activation in vivo
Modulation of the autonomic nervous system and behaviour by acute glial cell Gq protein-coupled receptor activation in vivo
复制标题
DOI：
10.1113/jphysiol.2013.261289
复制
发表时间：
2013-11-15
影响因子：
5.5
通讯作者：
McCarthy, Ken D.
中科院分区：
文献类型：
--
作者：
Agulhon, Cendra;Boyt, Kristen M.;McCarthy, Ken D.
胶质酸性蛋白（GFAP）表达细胞（GFAP（+）胶质细胞）是中枢和外周神经系统中的主要细胞类型。由于我们无法以细胞类型特异性和非侵入性的方式操纵这些细胞及其受体，我们对GFAP（+）胶质细胞及其信号系统在体内的作用的理解是有限的。为了克服这一限制，我们开发了一种转基因小鼠品系（GFAP-hM 3Dq小鼠），其在GFAP（+）胶质细胞中选择性地表达被称为hM 3Dq DREADD（设计者受体，仅由设计者药物激活）的工程化G（q）蛋白偶联受体（G（q）-GPCR）。hM 3Dq受体仅由生物惰性但生物可利用的配体（氯氮平-N-氧化物; CNO）激活，而对内源性GPCR配体无应答。在GFAP-hM 3Dq小鼠中，CNO给药增加了心率、血压和唾液形成，以及降低了体温，这些参数由自主神经系统（ANS）控制。此外，在CNO给药后观察到活动相关行为和运动协调的变化。遗传阻断肌醇1，4，5-三磷酸（IP 3）依赖性的星形胶质细胞中的Ca 2+增加未能干扰Hoc介导的ANS功能，运动活性或运动协调的变化。我们的研究结果揭示了GFAP（+）胶质细胞在体内调节复杂的生理和行为中的意外广泛作用，并表明这些作用不依赖于星形胶质细胞Ca 2+的IP 3依赖性增加。
Glial fibrillary acidic protein (GFAP)-expressing cells (GFAP(+) glial cells) are the predominant cell type in the central and peripheral nervous systems. Our understanding of the role of GFAP(+) glial cells and their signalling systems in vivo is limited due to our inability to manipulate these cells and their receptors in a cell type-specific and non-invasive manner. To circumvent this limitation, we developed a transgenic mouse line (GFAP-hM3Dq mice) that expresses an engineered G(q) protein-coupled receptor (G(q)-GPCR) known as hM3Dq DREADD (designer receptor exclusively activated by designer drug) selectively in GFAP(+) glial cells. The hM3Dq receptor is activated solely by a pharmacologically inert, but bioavailable, ligand (clozapine-N-oxide; CNO), while being non-responsive to endogenous GPCR ligands. In GFAP-hM3Dq mice, CNO administration increased heart rate, blood pressure and saliva formation, as well as decreased body temperature, parameters that are controlled by the autonomic nervous system (ANS). Additionally, changes in activity-related behaviour and motor coordination were observed following CNO administration. Genetically blocking inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ increases in astrocytes failed to interfere with CNO-mediated changes in ANS function, locomotor activity or motor coordination. Our findings reveal an unexpectedly broad role of GFAP(+) glial cells in modulating complex physiology and behaviour in vivo and suggest that these effects are not dependent on IP3-dependent increases in astrocytic Ca2+.