5-HT2A receptor dysregulation in a schizophrenia relevant mouse model of NMDA receptor hypofunction.
5-HT2A receptor dysregulation in a schizophrenia relevant mouse model of NMDA receptor hypofunction.
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精神分裂症相关NMDA受体功能低下的小鼠模型中5-HT2A受体的异常调节。
DOI：
10.1038/s41398-022-01930-0
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发表时间：
2022-04-22
影响因子：
6.8
通讯作者：
Nakazawa, Kazu
中科院分区：
文献类型：
--
作者：
Nakao, Kazuhito;Singh, Mahendra;Sapkota, Kiran;Fitzgerald, Andrew;Hablitz, John J.;Nakazawa, Kazu
阻断N-甲基-D-天冬氨酸受体(NMDAR)可以增强皮质5-羟色胺2A受体(5-HT2ARs)，这与精神病有关。然而，从NMDAR功能低下到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的快速刺激性中间神经元中，不可或缺的NMDAR亚单位Grin1的基因缺失是否可以上调5-HT2ARs，导致皮质的高兴奋性。首先，活体局部场电位记录显示，Grin1突变小鼠的听觉皮质在暴露于声波点击训练刺激后变得高度兴奋，皮质中释放了5-羟色胺。这种兴奋性的增加是在体外复制的，它包括突变的听觉皮质第2/3层锥体神经元动作电位(AP)放电频率的增加。应用5-HT2AR激动剂TCB-2也产生了类似的结果。5-HT2AR拮抗剂M100907在体内和体外均能逆转点击序列的作用。应用G-αQ蛋白抑制剂Bim-46187和G蛋白门控内向整流钾通道激动剂ML297也能逆转锥体神经元AP频率的增加。在快速放电的中间神经元中，5-HT2AR的激活通常会促进GABA的释放，导致突触后锥体神经元兴奋性降低，而突变体中缺失了这一点。此外，与对照组不同，GABAA受体拮抗剂(+)-荷包牡丹碱对突变锥体神经元的AP频率几乎没有影响，表明处于去抑制状态。这些结果表明，听觉诱导的高兴奋性状态是通过Grin1缺乏的中间神经元的GABA释放不足导致皮质锥体神经元的5-HT2AR调节失调和GIRK通道抑制而实现的，这可能与听性精神病有关。
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 GABAA 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.
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