Table6_Long-Term Enhancement of NMDA Receptor Function in Inhibitory Neurons Preferentially Modulates Potassium Channels and Cell Adhesion Molecules.XLS

Effectively enhancing the activity of inhibitory neurons has great therapeutic potentials since their reduced function/activity has significant contributions to pathology in various brain diseases. We showed previously that NMDAR positive allosteric modulator GNE-8324 and M-8324 selectively increase NMDAR activity on the inhibitory neurons and elevates their activity in vitro and in vivo. Here we examined the impact of long-term administering M-8324 on the functions and transcriptional profiling of parvalbumin-containing neurons in two representative brain regions, primary auditory cortex (Au1) and prelimbic prefrontal cortex (PrL-PFC). We found small changes in key electrophysiological parameters and RNA levels of neurotransmitter receptors, Na+ and Ca2+ channels. In contrast, large differences in cell adhesion molecules and K+ channels were found between Au1 and PrL-PFC in drug-naïve mice, and differences in cell adhesion molecules became much smaller after M-8324 treatment. There was also minor impact of M-8324 on cell cycle and apoptosis, suggesting a fine safety profile.

有效增强抑制性神经元的活性具有显著的诊疗潜力，鉴于其功能/活动的降低在多种脑部疾病的病理学中扮演着重要的角色。我们先前研究表明，NMDAR正性变构调节剂GNE-8324和M-8324能够选择性地提升抑制性神经元上的NMDAR活性，并在体外及体内提高其活性。在本研究中，我们探讨了长期给予M-8324对两个代表性脑区——初级听觉皮层（Au1）和前扣带回皮层（PrL-PFC）中含钙调蛋白神经元的功能和转录组学的影响。我们发现关键电生理参数和神经递质受体、钠离子（Na+）和钙离子（Ca2+）通道的RNA水平出现微小变化。然而，在未使用药物的小鼠中，Au1和PrL-PFC在细胞粘附分子和钾离子（K+）通道方面存在显著差异，而在M-8324治疗后，细胞粘附分子的差异显著减小。此外，M-8324对细胞周期和细胞凋亡的影响微乎其微，显示出良好的安全性特征。