INSERM U1114, Neuropsychologie Cognitive et Physiopathologie de la Schizophrénie, Strasbourg, France.; Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, FMTS, Faculté de Médecine, Strasbourg, France.; University of Freiburg, Bernstein Center Freiburg, Germany.
INSERM U1114, Neuropsychologie Cognitive et Physiopathologie de la Schizophrénie, Strasbourg, France.; Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, FMTS, Faculté de Médecine, Strasbourg, France.; Netherlands Institute for Neuroscience, Amsterdam, the Netherlands.
Schizophr Res. 2020 Aug;222:362-374. doi: 10.1016/j.schres.2020.04.029. Epub 2020 Jun 5.
In patients with psychotic disorders, sleep spindles are reduced, supporting the hypothesis that the thalamus and glutamate receptors play a crucial etio-pathophysiological role, whose underlying mechanisms remain unknown. We hypothesized that a reduced function of NMDA receptors is involved in the spindle deficit observed in schizophrenia.
An electrophysiological multisite cell-to-network exploration was used to investigate, in pentobarbital-sedated rats, the effects of a single psychotomimetic dose of the NMDA glutamate receptor antagonist ketamine in the sensorimotor and associative/cognitive thalamocortical (TC) systems.
Under the control condition, spontaneously-occurring spindles (intra-frequency: 10-16 waves/s) and delta-frequency (1-4 Hz) oscillations were recorded in the frontoparietal cortical EEG, in thalamic extracellular recordings, in dual juxtacellularly recorded GABAergic thalamic reticular nucleus (TRN) and glutamatergic TC neurons, and in intracellularly recorded TC neurons. The TRN cells rhythmically exhibited robust high-frequency bursts of action potentials (7 to 15 APs at 200-700 Hz). A single administration of low-dose ketamine fleetingly reduced TC spindles and delta oscillations, amplified ongoing gamma-(30-80 Hz) and higher-frequency oscillations, and switched the firing pattern of both TC and TRN neurons from a burst mode to a single AP mode. Furthermore, ketamine strengthened the gamma-frequency band TRN-TC connectivity. The antipsychotic clozapine consistently prevented the ketamine effects on spindles, delta- and gamma-/higher-frequency TC oscillations.
The present findings support the hypothesis that NMDA receptor hypofunction is involved in the reduction in sleep spindles and delta oscillations. The ketamine-induced swift conversion of ongoing TC-TRN activities may have involved at least both the ascending reticular activating system and the corticothalamic pathway.
在精神病患者中，睡眠梭形波减少，支持丘脑和谷氨酸受体在发病机制中起关键作用的假说，但其潜在机制尚不清楚。我们假设 NMDA 受体功能降低与精神分裂症中观察到的纺锤体减少有关。
使用电生理学多部位细胞-网络探测，在戊巴比妥钠麻醉的大鼠中，研究单次精神药物 NMDA 谷氨酸受体拮抗剂氯胺酮对感觉运动和联想/认知丘脑皮质（TC）系统的影响。
在对照条件下，在前顶叶皮质 EEG、丘脑细胞外记录、双共聚焦记录的 GABA 能丘脑网状核（TRN）和谷氨酸能 TC 神经元以及细胞内记录的 TC 神经元中，自发出现的纺锤波（内频：10-16 波/s）和 delta 频率（1-4 Hz）振荡。TRN 细胞节律性地产生强大的高频动作电位爆发（200-700 Hz 时有 7 到 15 个 AP）。单次低剂量氯胺酮短暂地减少了 TC 纺锤波和 delta 振荡，放大了正在进行的 gamma-（30-80 Hz）和更高频率的振荡，并将 TC 和 TRN 神经元的放电模式从爆发模式切换为单个 AP 模式。此外，氯胺酮增强了 gamma 频带 TRN-TC 连接。抗精神病药氯氮平一致地防止了氯胺酮对纺锤波、delta 和 gamma/更高频率 TC 振荡的影响。
本研究结果支持 NMDA 受体功能降低与睡眠纺锤波和 delta 振荡减少有关的假说。氯胺酮诱导的持续 TC-TRN 活动的快速转换可能至少涉及上行网状激活系统和皮质丘脑通路。
