Ekins Tyler G, Rybicki-Kler Chloe, Deng Tao, Brooks Isla A W, Jedrasiak-Cape Izabela, Donoho Ethan, Ahmed Omar J
Dept. of Psychology, University of Michigan, Ann Arbor, MI, 48109, USA.
Michigan Psychedelic Center, University of Michigan, Ann Arbor, MI, 48109, USA.
Mol Psychiatry. 2025 Sep 16. doi: 10.1038/s41380-025-03257-w.
Classical psychedelic drugs show promise as a treatment for major depressive disorder and related psychiatric disorders. This therapeutic efficacy stems from long-lasting psychedelic-induced neuroplasticity onto prefrontal cortical neurons and is thought to require the postsynaptic expression of serotonin 2A receptors (5-HTR). However, other cortical regions such as the granular retrosplenial cortex (RSG) - important for memory, spatial orientation, fear extinction, and imagining oneself in the future, but impaired in Alzheimer's disease - lack 5-HTR and are thus considered unlikely to benefit from psychedelic therapy. Here, we show that RSG pyramidal cells lacking postsynaptic 5-HT receptors still undergo long-lasting psychedelic-induced synaptic enhancement. A newly engineered CRISPR-Cas-based conditional knockout mouse line reveals that this form of psychedelic-induced retrosplenial plasticity requires presynaptic 5-HT receptors expressed on anterior thalamic axonal inputs to RSG. These results highlight a broader psychedelic therapeutic utility than currently appreciated, suggesting potential for augmenting RSG circuit function in Alzheimer's disease, post-traumatic stress disorder, and other neuropsychiatric conditions, despite the lack of postsynaptic 5-HT receptors.
经典的致幻药物有望用于治疗重度抑郁症及相关精神疾病。这种治疗效果源于致幻剂诱导的前额叶皮质神经元的持久神经可塑性，并且被认为需要5-羟色胺2A受体（5-HTR）在突触后表达。然而，其他皮质区域，如颗粒状压后皮质（RSG）——对记忆、空间定向、恐惧消退以及设想未来自我很重要，但在阿尔茨海默病中会受损——缺乏5-HTR，因此被认为不太可能从致幻疗法中获益。在此，我们表明缺乏突触后5-羟色胺受体的RSG锥体细胞仍会经历致幻剂诱导的持久突触增强。一种新设计的基于CRISPR-Cas的条件性基因敲除小鼠品系显示，这种形式的致幻剂诱导的压后可塑性需要在前丘脑轴突输入到RSG上表达的突触前5-羟色胺受体。这些结果凸显了比目前所认识到的更广泛的致幻治疗效用，表明尽管缺乏突触后5-羟色胺受体，但在阿尔茨海默病、创伤后应激障碍和其他神经精神疾病中增强RSG回路功能具有潜力。
