Maturation of GABAergic Synaptic Transmission From Neocortical Parvalbumin Interneurons Involves N-methyl-D-aspartate Receptor Recruitment of Cav2.1 Channels.
Maturation of GABAergic Synaptic Transmission From Neocortical Parvalbumin Interneurons Involves N-methyl-D-aspartate Receptor Recruitment of Cav2.1 Channels.
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新皮质小白蛋白中间神经元的 GABA 能突触传递的成熟涉及 Cav2.1 通道的 N-甲基-D-天冬氨酸受体募集。
DOI：
10.1016/j.neuroscience.2023.01.007
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发表时间：
2023
期刊：
影响因子：
3.3
通讯作者：
Nakazawa,Kazu
中科院分区：
文献类型：
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作者：
Singh,Mahendra;Sapkota,Kiran;Sakimura,Kenji;Kano,Masanobu;Cowell,RitaM;Overstreet-Wadiche,Linda;Hablitz,JohnJ;Nakazawa,Kazu
N-甲基-D-天冬氨酸受体(NMDAR)在脑发育过程中的功能低下可能是青壮年精神分裂症(SCZ)的表现之一。NMDAR功能低下的细胞靶点似乎至少部分是皮质边缘快峰(FS)中间神经元。然而，NMDAR功能低下后小白蛋白(PV)阳性FS中间神经元的功能变化尚不清楚。来自小鼠皮质PV中间神经元和锥体神经元的成对膜片钳记录显示，在出生后第二周之前，预期的PV中间神经元中NMDAR亚单位Grin1的基因缺失会损害诱发的和同步的GABA释放。而Grin1的缺失也干扰了固有的兴奋性和兴奋性，无论是通过阻断K+通道来恢复兴奋性，还是增加细胞外钙离子浓度，都不能挽救GABA的释放。GABA的释放对Cav2.1通道拮抗剂ω-agatoxin IVA也不敏感。在PV中间神经元中，Cacna基因(编码Cav2.1)的杂合缺失产生了与Grin1突变体相似的GABA释放表型。Cav2.1/2.2通道激动剂GV-58可增加Cacna 1a单倍体缺乏型PV中间神经元的体细胞钙电流和GABA释放，但不能增加Grin1缺失的PV中间神经元的GABA释放。综上所述，我们的结果表明，在预期的PV中间神经元中，Grin1的缺失损害了膜兴奋性的适当成熟和Cav2.1的招募，从而诱导了GABA的释放。这可能增加了主神经元的突触兴奋/抑制比，促进了SCZ样表型的出现。
N-methyl-D-aspartate receptor (NMDAR) hypofunction during brain development is likely to contribute to the manifestation of schizophrenia (SCZ) in young adulthood. The cellular targets of NMDAR hypofunction appear to be at least in part corticolimbic fast-spiking (FS) interneurons. However, functional alterations in parvalbumin (PV)-positive FS interneurons following NMDAR hypofunction are poorly understood. Paired patch-clamp recordings from murine cortical PV interneurons and pyramidal neurons revealed that genetic deletion of NMDAR subunitGrin1in prospective PV interneurons before the second postnatal week impaired evoked- and synchronized-GABA release. Whereas intrinsic excitability and spiking characteristics were also disturbed byGrin1deletion, neither restoring their excitability by K+channel blockade nor increasing extracellular Ca2+rescued the GABA release. GABA release was also insensitive to the Cav2.1 channel antagonist ω-agatoxin IVA. Heterozygous deletion ofCacna1agene (encoding Cav2.1) in PV interneurons produced a similar GABA release phenotype as theGrin1mutants. Treatment with the Cav2.1/2.2 channel agonist GV-58 augmented somatic Ca2+currents and GABA release inCacna1a-haploinsufficient PV interneurons, but failed to enhance GABA release in theGrin1-deleted PV interneurons. Taken together, our results suggest thatGrin1deletion in prospective PV interneurons impairs proper maturation of membrane excitability and Cav2.1-recruited evoked GABA release. This may increase synaptic excitatory/inhibitory ratio in principal neurons, contributing to the emergence of SCZ-like phenotypes.