Psychedelic neuroplasticity of cortical neurons lacking 5-HT2A receptors

Summary

Psychedelic drugs may help treat major depressive disorder and other psychiatric disorders by promoting neuroplasticity in the brain. This study shows that pyramidal cells in the granular retrosplenial cortex can still experience long-lasting synaptic enhancement from psychedelics, even without postsynaptic serotonin 2A receptors. Instead, presynaptic serotonin 2A receptors on thalamic inputs are necessary for this effect. These findings suggest that psychedelics could have therapeutic potential for conditions like Alzheimer’s disease and PTSD, despite the absence of certain receptors.

Study at a glance

Abstract

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-HT_2AR). 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-HT_2AR and are thus considered unlikely to benefit from psychedelic therapy. Here, we show that RSG pyramidal cells lacking postsynaptic 5-HT_2A 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_2A 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_2A receptors.