Nakao Kazuhito, Singh Mahendra, Sapkota Kiran, Fitzgerald Andrew, Hablitz John J, Nakazawa Kazu
Department of Neuroscience, Life Science Division, Southern Research, Birmingham, AL, 35205, USA.
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Transl Psychiatry. 2022 Apr 22;12(1):168. doi: 10.1038/s41398-022-01930-0.
Blockade of N-methyl-D-aspartate receptors (NMDAR) is known to augment cortical serotonin 2A receptors (5-HT2ARs), which is implicated in psychosis. However, the pathways from NMDAR hypofunction to 5-HT2AR up-regulation are unclear. Here we addressed in mice whether genetic deletion of the indispensable NMDAR-subunit Grin1 principally in corticolimbic parvalbumin-positive fast-spiking interneurons, could up-regulate 5-HT2ARs leading to cortical hyper-excitability. First, in vivo local-field potential recording revealed that auditory cortex in Grin1 mutant mice became hyper-excitable upon exposure to acoustic click-train stimuli that release 5-HT in the cortex. This excitability increase was reproduced ex vivo where it consisted of an increased frequency of action potential (AP) firing in layer 2/3 pyramidal neurons of mutant auditory cortex. Application of the 5-HT2AR agonist TCB-2 produced similar results. The effect of click-trains was reversed by the 5-HT2AR antagonist M100907 both in vivo and ex vivo. Increase in AP frequency of pyramidal neurons was also reversed by application of Gαq protein inhibitor BIM-46187 and G protein-gated inwardly-rectifying K (GIRK) channel activator ML297. In fast-spiking interneurons, 5-HT2AR activation normally promotes GABA release, contributing to decreased excitability of postsynaptic pyramidal neurons, which was missing in the mutants. Moreover, unlike the controls, the GABA receptor antagonist (+)-bicuculline had little effect on AP frequency of mutant pyramidal neurons, indicating a disinhibition state. These results suggest that the auditory-induced hyper-excitable state is conferred via GABA release deficits from Grin1-lacking interneurons leading to 5-HT2AR dysregulation and GIRK channel suppression in cortical pyramidal neurons, which could be involved in auditory psychosis.
已知阻断N-甲基-D-天冬氨酸受体（NMDAR）会增强皮质5-羟色胺2A受体（5-HT2AR），这与精神病有关。然而，从NMDAR功能减退到5-HT2AR上调的途径尚不清楚。在这里，我们在小鼠中研究了主要在皮质边缘小白蛋白阳性快速放电中间神经元中不可或缺的NMDAR亚基Grin1的基因缺失是否会上调5-HT2AR，导致皮质兴奋性过高。首先，体内局部场电位记录显示，Grin1突变小鼠的听觉皮质在暴露于能在皮质中释放5-羟色胺的听觉点击序列刺激时变得兴奋性过高。这种兴奋性增加在体外实验中得到重现，表现为突变体听觉皮质第2/3层锥体神经元动作电位（AP）发放频率增加。应用5-HT2AR激动剂TCB-2也产生了类似结果。无论是在体内还是体外，5-HT2AR拮抗剂M100907均可逆转点击序列的作用。应用Gαq蛋白抑制剂BIM-46187和G蛋白门控内向整流钾（GIRK）通道激活剂ML297也可逆转锥体神经元AP频率的增加。在快速放电中间神经元中，5-HT2AR激活通常会促进γ-氨基丁酸（GABA）释放，从而降低突触后锥体神经元的兴奋性，而突变体中则不存在这种情况。此外，与对照组不同，GABA受体拮抗剂（+）-荷包牡丹碱对突变体锥体神经元的AP频率影响很小，表明存在去抑制状态。这些结果表明，听觉诱导的兴奋性过高状态是通过缺乏Grin1的中间神经元释放GABA不足导致的，进而导致皮质锥体神经元中5-HT2AR失调和GIRK通道抑制，这可能与听觉性精神病有关。
