Downregulation of hyperpolarization‐activated cyclic nucleotide‐gated channels (HCN) in the hippocampus of patients with medial temporal lobe epilepsy and hippocampal sclerosis (MTLE‐HS)

Abstract

Changes in the expression of HCN ion channels leading to changes in Ih function and neuronal excitability are considered to be possible mechanisms involved in epileptogenesis in kinds of human epilepsy. In previous animal studies of febrile seizures and temporal lobe epilepsy, changes in the expression of HCN1 and HCN2 channels at different time points and in different parts of the brain were not consistent, suggesting that transcriptional disorders involving HCNs play a crucial role in the epileptogenic process. Therefore, we aimed to assess the transcriptional regulation of HCN channels in Medial temporal lobe epilepsy with hippocampal sclerosis (MTLE‐HS) patients. This study included eight nonhippocampal sclerosis patients and 40 MTLE‐HS patients. The mRNA expression of HCN channels was evaluated by qRT‐PCR, while the protein expression was quantitatively analyzed by Western blotting. The subcellular localization of HCN channels in the hippocampus was explored by immunofluorescence. We demonstrated that the mRNA and protein expression of HCN1 and HCN2 are downregulated in controls compared to that in MTLE‐HS patients. In the hippocampal CA1/CA4 subregion and GCL, in addition to a large decrease in neurons, the expression of HCN1 and HCN2 on neuronal cell membranes was also downregulated in MTLE‐HS patients. These findings suggest that the expression of HCN channels are downregulated in MTLE‐HS, which indicates that the decline in HCN channels in the hippocampus during chronic epilepsy in MTLE‐HS patients leads to the downregulation of Ih current density and function, thereby reducing the inhibitory effect and increasing neuronal excitability and eventually causing disturbances in the electrical activity of neurons.

The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review

“…The disruption of Ih current disturbs hippocampal theta function in rat models of temporal lobe epilepsy (Marcelin et al, 2009 ), and during seizures, there is a reduced expression of HCN1 channel and upregulation of HCN2 channel (Richichi et al, 2008 ). According to one study, messenger RNA and protein expression of HCN1 and HCN2 were downregulated in controls compared to the cases with medial temporal lobe epilepsy and hippocampal sclerosis (Lin et al, 2020 ). In these cases of mesial temporal lobe epilepsy with hippocampal sclerosis, the lowered expression of HCN1 and HCN2 during chronic phases reduces Ih current density and function, thereby decreasing inhibitory effects and enhancing neuronal excitability (Lin et al, 2020 ).…”

“…According to one study, messenger RNA and protein expression of HCN1 and HCN2 were downregulated in controls compared to the cases with medial temporal lobe epilepsy and hippocampal sclerosis (Lin et al, 2020 ). In these cases of mesial temporal lobe epilepsy with hippocampal sclerosis, the lowered expression of HCN1 and HCN2 during chronic phases reduces Ih current density and function, thereby decreasing inhibitory effects and enhancing neuronal excitability (Lin et al, 2020 ). The downregulation of HCN1 expression after seizures augments dendritic excitability, resulting in the development of temporal lobe epilepsy (Powell et al, 2008 ).…”

Presynaptic HCN channels constrain GABAergic synaptic transmission in pyramidal cells of the medial prefrontal cortex

“…The universality and nonselective cation permeability make HCN channels indispensable for cell excitability. Not only in pyramidal neurons, interneurons excitability homeostasis disorder also can trigger psychosis ( Choi et al, 2020 ; Lin et al, 2020 ). Simultaneously, HCN channels engage on intracellular coupling reaction, such as alpha-2 (α 2 ) adrenergic receptor, and the location of HCN channels in post-synapse membrane also facilitates their involvement in synaptic signaling ( Wang et al, 2007 ).…”

Effect of ivabradine on cognitive functions of rats with scopolamine-induced dementia

“…In the present study, the optical density of HCN1 immunoreactivity decreased significantly after ES in group III in different subfields of the hippocampus, indicating the involvement these channels in the Sco-induced neurodegeneration, similar to the effect of chronic cerebral hypoperfusion in rat 46 . Furthermore, the decrease in HCN1 and HCN2 expression in medial temporal lobe epilepsy with hippocampal sclerosis has been suggested to increase the susceptibility to seizures because it reduces the density of I h currents and enhance the excitability of neurons 47 . The pathogenetic mechanism underlies the neuronal discharge activity inconsistency is one of the main discussed hypotheses of the neurodegenerative diseases 48 .…”