Cannabidiol dampens propagation of hippocampal hyperactivity and differentially modulates feedforward and feedback inhibition
Year: 2025
Type: preprint
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.
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G2442437124, G2823830804, Synaptic and cellular mechanisms of neuronal synchronization, Medical Scientist Research Service Award, Targeting the LPI-GPR55 pathway to investigate the potential anti-seizure mechanism of cannabidiol, Calcium Channels, Calmodulin and Nuclear CREB Signaling, Neuronal Adaptation and Plasticity after Chronic Disuse, Synaptic Adaptation and Plasticity After Chronic Disuse
OpenAlex ID: W4413764337