Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States of America.
Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
PLoS One. 2020 May 21;15(5):e0233020. doi: 10.1371/journal.pone.0233020. eCollection 2020.
Signaling through the endocannabinoid system is critical to proper functioning of the cerebellar circuit. However, most studies have focused on signaling through cannabinoid type 1 (CB1) receptors, while relatively little is known about signaling through type 2 (CB2) receptors. We show that functional CB2 receptors are expressed in Purkinje cells using a combination of immunohistochemistry and patch-clamp electrophysiology in juvenile mice. Pharmacological activation of CB2 receptors significantly reduces inhibitory synaptic responses and currents mediated by photolytic uncaging of RuBi-GABA in Purkinje cells. CB2 receptor activation does not change the paired-pulse ratio of inhibitory responses and its effects are blocked by inclusion of GDP-β-S in the internal solution, indicating a postsynaptic mechanism of action. However, CB2 receptors do not contribute to depolarization induced suppression of inhibition (DSI), indicating they are not activated by endocannabinoids synthesized and released from Purkinje cells using this protocol. This work demonstrates that CB2 receptors inhibit postsynaptic GABAA receptors by a postsynaptic mechanism in Purkinje cells. This represents a novel mechanism by which CB2 receptors may modulate neuronal and circuit function in the central nervous system.
内源性大麻素系统的信号传递对于小脑回路的正常功能至关重要。然而，大多数研究都集中在大麻素 1 型 (CB1) 受体的信号传递上，而对 2 型 (CB2) 受体的信号传递知之甚少。我们使用免疫组织化学和在幼年小鼠中的膜片钳电生理学相结合的方法显示，功能性 CB2 受体在浦肯野细胞中表达。用光解 RuBi-GABA 对浦肯野细胞进行光解时，CB2 受体的药理学激活显著降低了抑制性突触反应和电流。CB2 受体的激活不会改变抑制性反应的成对脉冲比，并且其作用被包含在内部溶液中的 GDP-β-S 阻断，表明其作用机制是突触后。然而，CB2 受体不参与由使用该方案从浦肯野细胞合成和释放的内源性大麻素引起的去极化抑制 (DSI)，表明它们不会被 CB2 受体激活。这项工作表明，CB2 受体通过浦肯野细胞中的突触后机制抑制突触后 GABA A 受体。这代表了 CB2 受体在中枢神经系统中调节神经元和回路功能的一种新机制。
