Excitation of medium spiny neurons by 'inhibitory' ultrapotent chemogenetics via shifts in chloride reversal potential.
Excitation of medium spiny neurons by 'inhibitory' ultrapotent chemogenetics via shifts in chloride reversal potential.
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DOI：
10.7554/elife.64241
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发表时间：
2021-04-06
期刊：
影响因子：
7.7
通讯作者：
Moussawi K
中科院分区：
文献类型：
--
作者：
Gantz SC;Ortiz MM;Belilos AJ;Moussawi K
超强效化学遗传学，包括氯渗透性抑制性PSAM 4-GlyR受体，最近被提出作为一种强大的策略，选择性地控制清醒，行为动物的神经元活动。我们的目的是验证PSAM 4-GlyR在腹侧纹状体多巴胺D1受体表达的中型棘神经元（D1-MSNs）中的抑制功能。用uPSEM 792配体激活PSAM 4-GlyR增强而不是抑制D1-MSN的体内活性，如通过D1-MSN中增加的c-fos表达所指示的，以及体外活性，如通过小鼠脑切片中来自D1-MSN的细胞附着记录所指示的。全细胞记录显示，PSAM 4-GlyR的激活使D1-MSN去极化，减弱GABA能抑制，并将PSAM 4-GlyR电流的逆转电位转移到更多的去极化电位，使受体激活的去极化效应持续存在。这些数据表明，“抑制性”PSAM 4-GlyR化学遗传学可能激活某些细胞类型，并突出了利用氯离子电导抑制神经元的陷阱。
Ultrapotent chemogenetics, including the chloride-permeable inhibitory PSAM4-GlyR receptor, were recently proposed as a powerful strategy to selectively control neuronal activity in awake, behaving animals. We aimed to validate the inhibitory function of PSAM4-GlyR in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) in the ventral striatum. Activation of PSAM4-GlyR with the uPSEM792 ligand enhanced rather than suppressed the activity of D1-MSNs in vivo as indicated by increased c-fos expression in D1-MSNs and in vitro as indicated by cell-attached recordings from D1-MSNs in mouse brain slices. Whole-cell recordings showed that activation of PSAM4-GlyR depolarized D1-MSNs, attenuated GABAergic inhibition, and shifted the reversal potential of PSAM4-GlyR current to more depolarized potentials, perpetuating the depolarizing effect of receptor activation. These data show that ‘inhibitory’ PSAM4-GlyR chemogenetics may activate certain cell types and highlight the pitfalls of utilizing chloride conductances to inhibit neurons.