Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10065.
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10065
J Neurosci. 2019 Jun 26;39(26):5234-5242. doi: 10.1523/JNEUROSCI.0950-18.2019. Epub 2019 Apr 26.
Hypofunction of NMDA receptors has been considered a possible cause for the pathophysiology of schizophrenia. More recently, indirect ways to regulate NMDA that would be less disruptive have been proposed and metabotropic glutamate receptor subtype 5 (mGluR5) represents one such candidate. To characterize the cell populations involved, we demonstrated here that knock-out (KO) of mGluR5 in cholinergic, but not glutamatergic or parvalbumin (PV)-positive GABAergic, neurons reduced prepulse inhibition of the startle response (PPI) and enhanced sensitivity to MK801-induced locomotor activity. Inhibition of cholinergic neurons in the medial septum by DREADD (designer receptors exclusively activated by designer drugs) resulted in reduced PPI further demonstrating the importance of these neurons in sensorimotor gating. Volume imaging and quantification were used to compare PV and cholinergic cell distribution, density, and total cell counts in the different cell-type-specific KO lines. Electrophysiological studies showed reduced NMDA receptor-mediated currents in cholinergic neurons of the medial septum in mGluR5 KO mice. These results obtained from male and female mice indicate that cholinergic neurons in the medial septum represent a key cell type involved in sensorimotor gating and are relevant to pathologies associated with disrupted sensorimotor gating such as schizophrenia. The mechanistic complexity underlying psychiatric disorders remains a major challenge that is hindering the drug discovery process. Here, we generated genetically modified mouse lines to better characterize the involvement of the receptor mGluR5 in the fine-tuning of NMDA receptors, specifically in the context of sensorimotor gating. We evaluated the importance of knocking-out mGluR5 in three different cell types in two brain regions and performed different sets of experiments including behavioral testing and electrophysiological recordings. We demonstrated that cholinergic neurons in the medial septum represent a key cell-type involved in sensorimotor gating. We are proposing that pathologies associated with disrupted sensorimotor gating, such as with schizophrenia, could benefit from further evaluating strategies to modulate specifically cholinergic neurons in the medial septum.
NMDA 受体功能低下被认为是精神分裂症病理生理学的一个可能原因。最近，人们提出了一些间接调节 NMDA 的方法，这些方法的破坏性更小，代谢型谷氨酸受体 5（mGluR5）就是这样一种候选药物。为了确定涉及的细胞群体，我们在这里证明，在胆碱能神经元中敲除 mGluR5（但不在谷氨酸能神经元或 PV 阳性 GABA 能神经元中敲除）会降低惊吓反应的前脉冲抑制（PPI），并增强 MK801 诱导的运动活性的敏感性。通过 DREADD（专门被设计药物激活的设计受体）抑制中隔核中的胆碱能神经元，进一步证明了这些神经元在感觉运动门控中的重要性，导致 PPI 降低。体积成像和定量用于比较不同细胞类型特异性 KO 系中的 PV 和胆碱能神经元的分布、密度和总细胞计数。电生理研究表明，mGluR5 KO 小鼠中中隔核中的胆碱能神经元的 NMDA 受体介导的电流减少。这些来自雄性和雌性小鼠的结果表明，中隔核中的胆碱能神经元是参与感觉运动门控的关键细胞类型，与感觉运动门控障碍相关的病理学有关，例如精神分裂症。精神疾病的发病机制仍然是一个主要挑战，阻碍了药物发现过程。在这里，我们生成了基因修饰的小鼠系，以更好地描述中隔核中的受体 mGluR5 如何参与 NMDA 受体的微调，特别是在感觉运动门控的背景下。我们评估了在两个脑区的三种不同细胞类型中敲除 mGluR5 的重要性，并进行了不同的实验，包括行为测试和电生理记录。我们证明，中隔核中的胆碱能神经元是参与感觉运动门控的关键细胞类型。我们提出，与感觉运动门控障碍相关的病理学，例如精神分裂症，可以从进一步评估专门调节中隔核中胆碱能神经元的策略中受益。
