The 5-HT5A Receptor Regulates Excitability in the Auditory Startle Circuit: Functional Implications for Sensorimotor Gating
The 5-HT5A Receptor Regulates Excitability in the Auditory Startle Circuit: Functional Implications for Sensorimotor Gating
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DOI：
10.1523/jneurosci.4733-12.2013
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发表时间：
2013-06-12
影响因子：
5.3
通讯作者：
Preuss, Thomas
中科院分区：
文献类型：
--
作者：
Curtin, Paul C. P.;Medan, Violeta;Preuss, Thomas
在这里，我们应用行为测试，药理学和体内电生理学来确定5-羟色胺5-HT 5A受体在金鱼惊吓可塑性和感觉运动门控中的功能。在最初的一系列行为实验中，我们表征了选择性5-HT 5A拮抗剂SB-699551（3-环戊基-N-[2-（二甲氨基）乙基]-N-[（4 '-{[（2-苯乙基）氨基]甲基}-4-联苯基）甲基]丙酰胺二盐酸盐）对声惊吓反应的前脉冲抑制的作用。这些实验表明，在前脉冲条件下，惊吓率呈剂量依赖性下降。随后的行为实验表明，SB-699551还降低了基线惊吓率（即，没有预脉冲）。为了确定这些行为背后的细胞机制，我们测试了两种不同的选择性5-HT 5A拮抗剂SB-699551和A-843277（N-（2，6-二甲氧基苄基）-N '[4-（4-氟苯基）噻唑-2-基]胍）对毛特纳细胞（M-细胞）（惊吓回路的决策神经元）的固有膜特性和突触声音反应的影响。在用任一5-HT 5A拮抗剂处理后，M细胞中记录的听觉诱发突触后电位的衰减相似（SB-699551，降低26.41 +/- 3.98%; A-843277，降低17.52 +/- 6.24%）。这种衰减是由M细胞输入电阻的强直性（内在）降低产生的，可能由Cl-电导介导，这增加了由听觉前脉冲产生的外在抑制。有趣的是，神经前脉冲抑制本身的效应机制不受拮抗剂治疗。总之，这些结果提供了一个在体内的5-HT 5A受体和其行为的相关性的电生理特性，并提供了一个新的视角在惊吓可塑性和感觉运动门控的内在和外在的调制机制的相互作用。
Here we applied behavioral testing, pharmacology, and in vivo electrophysiology to determine the function of the serotonin 5-HT5A receptor in goldfish startle plasticity and sensorimotor gating. In an initial series of behavioral experiments, we characterized the effects of a selective 5-HT5A antagonist, SB-699551 (3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4'-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride), on prepulse inhibition of the acoustic startle response. Those experiments showed a dose-dependent decline in startle rates in prepulse conditions. Subsequent behavioral experiments showed that SB-699551 also reduced baseline startle rates (i.e., without prepulse). To determine the cellular mechanisms underlying these behaviors, we tested the effects of two distinct selective 5-HT5A antagonists, SB-699551 and A-843277 (N-(2,6-dimethoxybenzyl)-N'[4-(4-fluorophenyl)thiazol-2-yl]guanidine), on the intrinsic membrane properties and synaptic sound response of the Mauthner cell (M-cell), the decision-making neuron of the startle circuit. Auditory-evoked postsynaptic potentials recorded in the M-cell were similarly attenuated after treatment with either 5-HT5A antagonist (SB-699551, 26.41 +/- 3.98% reduction; A-843277, 17.52 +/- 6.24% reduction). This attenuation was produced by a tonic (intrinsic) reduction in M-cell input resistance, likely mediated by a Cl- conductance, that added to the extrinsic inhibition produced by an auditory prepulse. Interestingly, the effector mechanisms underlying neural prepulse inhibition itself were unaffected by antagonist treatment. In summary, these results provide an in vivo electrophysiological characterization of the 5-HT5A receptor and its behavioral relevance and provide a new perspective on the interaction of intrinsic and extrinsic modulatory mechanisms in startle plasticity and sensorimotor gating.