Aberrant HCN4 channel expression: Impacts on neuronal excitability and implications for epilepsy pathogenesis

Area of Science:

• Neuroscience
• Channelopathies
• Molecular Biology

Background:

• Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are voltage-gated cation channels with four isoforms (HCN1-4).
• HCN4 channels are known for cardiac pacemaker activity but also play significant roles in brain function, particularly in subcortical regions.
• Pathogenic variants in HCN4 are linked to cardiac abnormalities, and its expression is implicated in neurological disorders.

Purpose of the Study:

• To review the function of HCN4 channels in the brain.
• To focus on their roles in modulating neuronal and network-level excitability.
• To discuss the link between HCN4 channel dysfunction and epilepsy, and evaluate therapeutic strategies targeting HCN4.

Main Methods:

• Review of existing literature from clinical studies and animal models.
• Analysis of the canonical functions of HCN4 channels in regulating rhythmic and oscillatory activity.
• Evaluation of evidence linking aberrant HCN4 expression to hyperexcitability disorders.

Main Results:

• HCN4 channels are predominantly expressed in subcortical brain regions.
• They regulate critical neuronal functions, including transmitter release, burst firing, and network oscillations.
• Aberrant HCN4 expression is associated with increased seizure susceptibility and hyperexcitability in conditions like focal cortical dysplasia and tuberous sclerosis.

Conclusions:

• HCN4 channels play a vital role in modulating brain excitability at both individual neuron and network levels.
• Dysregulation of HCN4 channels is implicated in the pathophysiology of epilepsy.
• Targeting HCN4 channels presents a promising therapeutic avenue for seizure control.