FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.
Center for Brain Science, Department of Molecular Cellular Biology, Harvard University, 52 Oxford Street, Cambridge, MA, 02138, USA.
Mol Psychiatry. 2019 Jun;24(6):828-838. doi: 10.1038/s41380-018-0341-9. Epub 2019 Jan 29.
Ketamine has emerged as a widespread treatment for a variety of psychiatric disorders when used at sub-anesthetic doses, but the neural mechanisms underlying its acute action remain unclear. Here, we identified NMDA receptors containing the 2A subunit (GluN2A) on parvalbumin (PV)-expressing inhibitory interneurons as a pivotal target of low-dose ketamine. Genetically deleting GluN2A receptors globally or selectively from PV interneurons abolished the rapid enhancement of visual cortical responses and gamma-band oscillations by ketamine. Moreover, during the follicular phase of the estrous cycle in female mice, the ketamine response was transiently attenuated along with a concomitant decrease of grin2A mRNA expression within PV interneurons. Thus, GluN2A receptors on PV interneurons mediate the immediate actions of low-dose ketamine treatment, and fluctuations in receptor expression across the estrous cycle may underlie sex-differences in drug efficacy.
氯胺酮在亚麻醉剂量下被广泛应用于治疗各种精神疾病，但它的急性作用的神经机制仍不清楚。在这里，我们确定了含有 2A 亚基的 NMDA 受体（GluN2A）在表达 Parvalbumin（PV）的抑制性中间神经元上，是低剂量氯胺酮的关键靶点。从全局或选择性地从 PV 中间神经元中敲除 GluN2A 受体，可消除氯胺酮对视觉皮层反应和γ波段振荡的快速增强作用。此外，在雌性小鼠动情周期的卵泡期，氯胺酮的反应随着 PV 中间神经元内 Grin2A mRNA 表达的伴随减少而短暂减弱。因此，PV 中间神经元上的 GluN2A 受体介导了低剂量氯胺酮治疗的即时作用，而受体表达在动情周期中的波动可能是药物疗效性别差异的基础。
