Psychedelics Reverse the Polarity of Long-Term Synaptic Plasticity in Cortical-Projecting Claustrum Neurons

Psychedelic drugs like DOI can reverse the direction of synaptic plasticity in the claustrum, a brain region rich in serotonin 2 receptors and heavily connected to the anterior cingulate cortex. In male rats, pairing presynaptic stimuli with postsynaptic action potentials in claustrum neurons projecting to the ACC caused DOI to flip the plasticity from long-term depression to long-term potentiation, an effect specific to locally activated synapses. DOI also altered several action potential dynamics in these neurons. The findings support the idea that psychedelics induce rapid and lasting neuroplasticity and that claustrocortical circuits are especially sensitive to these drugs, offering a potential mechanism for their therapeutic effects.

Study at a glance

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 presynaptic stimuli paired with postsynaptic action potentials (APs) to a subpopulation of CLA neurons projecting to ACC in male rats to find that the psychedelic drug, 2,5-dimethoxy-4-iodoamphetamine (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 AP dynamics induced by DOI. These findings align with the view that psychedelics induce rapid and lasting synaptic plasticity and strengthen the hypothesis that claustrocortical circuits are highly sensitive to psychedelic drug action.