Cannabidiol attenuates seizure progression and recognition memory deficit induced by hippocampal HCN₁ knockdown in...

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.