Cannabidiol Attenuates Seizure Progression and Recognition Memory Deficit Induced by Hippocampal HCN(1) Knockdown in the Kindling Model of Epilepsy in Male Rats.

内容摘要

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.