Ly Calvin, Greb Alexandra C, Vargas Maxemiliano V, Duim Whitney C, Grodzki Ana Cristina G, Lein Pamela J, Olson David E
Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California, Davis 95616, United States.
Neuroscience Graduate Program, University of California, Davis, Davis, California 95618, United States.
ACS Pharmacol Transl Sci. 2020 Sep 11;4(2):452-460. doi: 10.1021/acsptsci.0c00065. eCollection 2021 Apr 9.
Cortical neuron atrophy is a hallmark of depression and includes neurite retraction, dendritic spine loss, and decreased synaptic density. Psychoplastogens, small molecules capable of rapidly promoting cortical neuron growth, have been hypothesized to produce long-lasting positive effects on behavior by rectifying these deleterious structural and functional changes. Here we demonstrate that ketamine and LSD, psychoplastogens from two structurally distinct chemical classes, promote sustained growth of cortical neurons after only short periods of stimulation. Furthermore, we show that psychoplastogen-induced cortical neuron growth can be divided into two distinct epochs: an initial stimulation phase requiring TrkB activation and a growth period involving sustained mTOR and AMPA receptor activation. Our results provide important temporal details concerning the molecular mechanisms by which next-generation antidepressants produce persistent changes in cortical neuron structure, and they suggest that rapidly excreted psychoplastogens might still be effective neurotherapeutics with unique advantages over compounds like ketamine and LSD.
皮质神经元萎缩是抑郁症的一个标志，包括神经突回缩、树突棘丢失和突触密度降低。心理塑型剂是一类能够快速促进皮质神经元生长的小分子，据推测，它们可通过纠正这些有害的结构和功能变化，对行为产生持久的积极影响。在此，我们证明，氯胺酮和麦角酸二乙酰胺（LSD）这两种来自结构不同化学类别的心理塑型剂，仅在短时间刺激后就能促进皮质神经元的持续生长。此外，我们表明，心理塑型剂诱导的皮质神经元生长可分为两个不同阶段：一个是需要TrkB激活的初始刺激阶段，另一个是涉及mTOR和AMPA受体持续激活的生长阶段。我们的研究结果提供了有关下一代抗抑郁药在皮质神经元结构上产生持久变化的分子机制的重要时间细节，并且表明，与氯胺酮和LSD等化合物相比，能快速排泄的心理塑型剂可能仍是具有独特优势的有效神经治疗药物。
