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bioRxiv · 10.1101/2025.08.26.672420

Cannabidiol dampens propagation of hippocampal hyperactivity and differentially modulates feedforward and feedback inhibition

Chamberland, S.·Rosenberg, E. C.·Nebet, E. R.·Devinsky, O.·Tsien, R. W.
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Abstract

Cannabidiol (CBD) decreases seizures in patients with severe pediatric-onset epilepsies including Dravet, Lennox-Gastaut, and Tuberous Sclerosis syndromes. However, the effects of CBD on neuronal activity and circuits remain obscure. In the mouse hippocampus, we found that CBD causes a GPR55-independent decrease in CA1 pyramidal neuron firing frequency and a GPR55-dependent reduction in CA3 to CA1 hippocampal activity propagation. CBD-mediated decrease in high-frequency activity was mimicked by GPR55 antagonism and prevented by GPR55 deletion and blockade of GABAergic transmission. Dampening high-frequency activity was accompanied by increased recruitment of parvalbumin+ (PV)-INs and reduced recruitment of somatostatin+ (SST)-INs, leveraging the inhibitory subcircuit to limit propagation of hyperactivity. CBD-induced attenuation of high frequency spike propagation was mimicked by pharmacological enhancement and optogenetic engagement of PV-INs. Such increased on-demand recruitment of PV-INs dampened propagation of high-frequency activity to hippocampal CA1 similarly to CBD. We predict that CBD potentially curbs propagation and perpetuation of seizure activity via these mechanisms.

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Chamberland, S., Rosenberg, E. C., Nebet, E. R., Devinsky, O., Tsien, R. W.. 2025-08-27. Cannabidiol dampens propagation of hippocampal hyperactivity and differentially modulates feedforward and feedback inhibition. https://doi.org/10.1101/2025.08.26.672420

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