Department of Psychiatry and Psychotherapy, Psychiatry Neuroimaging Branch (PNB), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Center of Psychiatry, Justus-Liebig University, 35392 Giessen, Germany.
Int J Mol Sci. 2023 Jan 18;24(3):1913. doi: 10.3390/ijms24031913.
NMDA-receptor hypofunction is increasingly considered to be an important pathomechanism in schizophrenia. However, to date, it has not been possible to identify patients with relevant NMDA-receptor hypofunction who would respond to glutamatergic treatments. Preclinical models, such as the ketamine model, could help identify biomarkers related to NMDA-receptor function that respond to glutamatergic modulation, for example, via activation of the glycine-binding site. We, therefore, aimed to investigate the effects of opposing modulation of the NMDA receptor on gamma activity (30-100 Hz) at rest, the genesis of which appears to be highly dependent on NMDA receptors. The effects of subanesthetic doses of S-ketamine and pretreatment with glycine on gamma activity at rest were examined in twenty-five healthy male participants using 64-channel electroencephalography. Psychometric scores were assessed using the PANSS and the 5D-ASC. While S-ketamine significantly increased psychometric scores and gamma activity at the scalp and in the source space, pretreatment with glycine did not significantly attenuate any of these effects when controlled for multiple comparisons. Our results question whether increased gamma activity at rest constitutes a suitable biomarker for the target engagement of glutamatergic drugs in the preclinical ketamine model. They might further point to a differential role of NMDA receptors in gamma activity generation.
NMDA 受体功能低下被认为与精神分裂症的发病机制有关。然而，迄今为止，尚未能够识别出具有相关 NMDA 受体功能低下且对谷氨酸能治疗有反应的患者。临床前模型，如氯胺酮模型，可帮助确定与 NMDA 受体功能相关的生物标志物，这些标志物可通过激活甘氨酸结合位点来响应谷氨酸能调节。因此，我们旨在研究 NMDA 受体的相反调节对静息状态下γ活动（30-100 Hz）的影响，γ活动的产生似乎高度依赖于 NMDA 受体。使用 64 通道脑电图，我们在 25 名健康男性参与者中检查了亚麻醉剂量 S-氯胺酮和甘氨酸预处理对静息状态下γ活动的影响。使用 PANSS 和 5D-ASC 评估心理测量评分。S-氯胺酮显著增加了头皮和源空间的心理测量评分和γ活动，而在进行多次比较控制后，甘氨酸预处理并没有显著减弱这些影响。我们的结果质疑静息状态下增加的γ活动是否构成了临床前氯胺酮模型中谷氨酸能药物的靶标结合的合适生物标志物。它们可能进一步表明 NMDA 受体在γ活动产生中的作用不同。
