CLASSICAL PSYCHEDELICS DISRUPT SYNAPTIC AND SPIKING ACTIVITY IN THE MOUSE DORSAL HIPPOCAMPUS

Classical psychedelics such as LSD and psilocybin are known to profoundly alter perception and cognition primarily by binding to the serotonin 2A receptor (5-HT2AR). However, the neuronal and circuit mechanisms underlying these effects remain poorly understood. Here, we investigated the impact of several classical psychedelics and non-hallucinogenic 5-HT2AR agonists on LFP and neuronal activity in the mouse dorsal hippocampus. Using Neuropixels 1.0 probes, we performed acute electrophysiological recordings in head‑fixed animals freely behaving in a Neurotar system. Animals were recorded for two hours and received three escalating doses, separated by 30 minutes, of either a classical psychedelic, a non-hallucinogenic 5-HT2AR agonist, or saline (3-7 recordings with each compound, > 40 recordings in total). Hippocampal layers and subregions were identified using established LFP landmarks, including theta oscillations, sharp wave-ripples, dentate spikes, and current source density profiles. Classical psychedelics reliably reduced broadband LFP power, altered sharp wave-ripple and dentate spike activity, and decreased CA1 neuronal firing. Critically, these changes were accompanied by a robust disruption of theta-gamma (30–90 Hz) phase-amplitude coupling across CA1 and DG layers, suggesting an impaired coordination of hippocampal communication rather than a global suppression of oscillatory activity. These effects were not observed following administration of non‑hallucinogenic 5‑HT2AR agonists or saline. Our findings indicate that classical psychedelics exert strong modulatory effects not only in the ventral hippocampus, as reported previously, but also in the dorsal hippocampus, despite its relatively low 5-HT2AR expression, highlighting hippocampal circuit disorganisation as a potential core feature of the psychedelic state.