“Epilepsy is a neurological disorder characterized by excessive neuronal firing, frequently originating in the hippocampus. Hyperpolarization-activated cyclic nucleotide-gated channel-1 (HCN₁) regulates neuronal excitability and resting membrane potential, yet its role in seizure progression remains unclear.

Cannabidiol (CBD), an effective anticonvulsant, may exert part of its effects through HCN₁.

This study investigated the contribution of HCN₁ to seizure progression, synaptic plasticity, and CBD-mediated neuroprotection.

Rats were implanted with stimulation electrodes in the perforant path (PP) and recording electrodes with a guide cannula in the dentate gyrus (DG). One week later, lentiviral shRNA-HCN₁ was injected into the DG, followed by PP electrical kindling. CBD (100 ng/2 μL) was administered every other day in shRNA-HCN₁-treated or non-manipulated animals. Seizure severity was assessed using Racine’s scale. Synaptic transmission, paired-pulse plasticity, and long-term potentiation (LTP) were evaluated by extracellular field recordings, HCN₁ function by whole-cell patch-clamp recordings of Ih (Hyperpolarization-activated current), HCN₁ expression by RT-qPCR, and recognition memory using the novel object recognition (NOR) test.

Kindling reduced HCN₁ mRNA expression, which was further decreased by shRNA-HCN₁. HCN₁ knockdown accelerated seizure progression, prolonged after-discharge duration, increased spike activity, reduced the sag ratio, and impaired synaptic transmission, paired-pulse plasticity, LTP, and object recognition memory in fully kindled rats.

CBD significantly attenuated these electrophysiological and recognition memory deficits, although its protective effects were partially reduced following HCN₁ knockdown.

These findings indicate that HCN₁ contributes to seizure progression and hippocampal dysfunction, while CBD exerts anticonvulsant and neuroprotective effects through both HCN₁-dependent and HCN₁-independent mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/42532179

“CBD attenuates seizure severity and rescues recognition memory deficits.”

“This study provides direct experimental evidence that hippocampal HCN₁ channels play a vital protective role against seizure progression and recognition memory disturbance in the kindling model. Furthermore, we found that the functional involvement of these channels in the DG is an essential and novel mechanism underlying the anticonvulsant and neuroprotective effects of CBD.”

https://www.sciencedirect.com/science/article/abs/pii/S0028390826002893?via%3Dihub