Psychedelics reverse the polarity of long-term synaptic plasticity in cortical-projecting claustrum neurons

eNeuro. 2025 Oct 27:ENEURO.0047-25.2025. doi: 10.1523/ENEURO.0047-25.2025. Online ahead of print.

ABSTRACT

Psychedelic drugs have garnered increasing attention for their therapeutic potential in treating a variety of psychiatric diseases, such as depression, anxiety, and substance use disorder. The claustrum (CLA), a brain area with remarkable interconnectivity to frontal cortices, has recently been shown to have a dense population of serotonin 2 receptors (5-HT2Rs) that are activated by psychedelics. Because psychedelic therapy can require as little as one treatment session, it has been speculated that psychedelics achieve their long-term remedial effects by inducing neuroplasticity in brain areas responsible for psychiatric disease states, such as the anterior cingulate cortex (ACC). However, the effects of psychedelics on synaptic plasticity in serotonin receptor-rich brain areas remain entirely unexplored. We applied pre-synaptic stimuli paired with post-synaptic action potentials to a subpopulation of CLA neurons projecting to ACC in male rats to find that the psychedelic drug, DOI, reverses the polarity of synaptic plasticity from long-term depression (LTD) to long-term potentiation (LTP) in a manner that may reflect contribution of excitatory or inhibitory neurotransmission, but is specific to synapses activated by local electrical stimulation. Additionally, we characterize intrinsic electrophysiological properties of CLA-ACC neurons with and without DOI application, noting several changes to action potential dynamics induced by DOI. These findings align with the view that psychedelics induce rapid and lasting synaptic plasticity and strengthen the hypothesis that claustro-cortical circuits are highly sensitive to psychedelic drug action.Significance Statement Psychedelics are showing promise for treatment of various psychiatric disorders. How do psychedelics promote long-term therapeutic changes in the brain? A leading theory is that lasting neuronal plasticity is induced by psychedelic drug action at 5-HT2Rs. Here, we evaluate neurons in the claustrum, a region with the highest density of 5-HT2Rs in the brain. We report that the psychedelic, DOI, provokes a net change in synaptic efficacy that manifests as long-term potentiation of excitatory post-synaptic potentials instead of the long-term depression observed under control conditions. These results provide a possible cellular excitability basis of long-term psychedelic drug action.

PMID:41145210 | DOI:10.1523/ENEURO.0047-25.2025