Table 3.

HCN subtypes directly and indirectly related to epilepsy in animal models.

Gene	Animal model for epilepsy	Phenotype	Key findings
HCN1	KO (Nishitani et al., 2019)	Absence epilepsy (Nishitani et al., 2019)	Reduction of Ih current in the cortical and hippocampal pyramidal neurons, pronounced hyperpolarizing shift of the resting membrane potential, and increased input resistance. Prone to pentylenetetrazol-induced acute convulsions. Showed spontaneous spike-wave discharges and behavioral arrest (Nishitani et al., 2019).
	KO (Saito et al., 2012)	Epileptic seizures (Saito et al., 2012)	Ablation of HCN1 in mice augmented the production of amyloid-β peptide (Aβ) (Saito et al., 2012).
	Adult HCN1-null mice (Huang et al., 2009)	Kainic acid-induced seizures (Huang et al., 2009)	Loss of dendritic HCN1 subunits which resulted in the enhanced cortical excitability and the development of epilepsy (Huang et al., 2009).
	GABAAγ2 (R43Q) mouse (Phillips et al., 2014)	Absence epilepsy (Phillips et al., 2014)	Diminished hippocampal HCN1 expression and function as well as spatial learning deficit (Phillips et al., 2014).
	HCN1-deficient rats (Nishitani et al., 2020)	Absence seizures, loose muscle tension, and abnormal gait (Nishitani et al., 2020).	HCN1 is involved in motor coordination and muscle strength (Boychuk and Teskey, 2017; Boychuk et al., 2017; Nishitani et al., 2020).
	HCN1 M294L heterozygous knock-in (HCN1M294L) mouse (Bleakley et al., 2021)	Severe developmental impairment and drug-resistant epilepsy (Bleakley et al., 2021)	The mechanism of epilepsy is continuous cation leak that resulted in hyperexcitability of the layer V somatosensory cortical pyramidal neurons (Bleakley et al., 2021).
HCN2	HCN2-null mice (Ludwig et al., 2003)	Absence seizures (105)	HCN2-deficient mice demonstrated spontaneous absence seizures. The thalamocortical relay had complete loss of the HCN current thus increased hyperexcitabilty. This was accompanied with dysrhythmia (Ludwig et al., 2003).
	HCN2 knock-in mouse model (HCN2EA) (Hammelmann et al., 2019).	Absence seizures and learning disability (Hammelmann et al., 2019).	cAMP regulates HCN2 channel (Hammelmann et al., 2019).
HCN4	Conditional HCN4 –KO model (Kharouf et al., 2020a).	Seizures (Kharouf et al., 2020a)	EC18 and HCN4-KO reduced seizure susceptibility (Kharouf et al., 2020a).
	GSK3β [S9A] mice (Urbanska et al., 2019)	Kainic acid-induced seizures (Urbanska et al., 2019)	GSK3β regulates HCN4 level and the expression of synaptic AMPA receptors (Urbanska et al., 2019).
TRIP8b	TRIP8b KO (Heuermann et al., 2016)	Absence seizures (Heuermann et al., 2016)	Decreased HCN channel expression and function in thalamic-projecting cortical layer 5b neurons and thalamic relay neurons. Preserved HCN function in inhibitory neurons of the reticular thalamic nucleus (Heuermann et al., 2016).
	TRIP8b-null mice (Huang et al., 2012).	Kainic acid-induced seizures (Huang et al., 2012)	Presynaptic adult cortical HCN channel expression continually diminished following induction of seizures and not dendritic HCN channels. Modulation of the adult presynaptic cortical HCN expression is independent of TRIP8b (Huang et al., 2012).
Others	Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model (Cain et al., 2015)	Absence seizures (Cain et al., 2015)	Increased HCN-1 and HCN-3 expression in ventrobasal thalamic neurons and the blockage of Ih current suppressed burst-firing (usually accompany spike-and-wave discharges) (Cain et al., 2015).
	Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model (Kuisle et al., 2006)	Absence seizures (Kuisle et al., 2006)	The binding of cAMP to HCN channels was weakened in acute phase thus promoted epilepsy and the compensatory mechanisms to stabilize Ih current activity led to the cessation of spike-and-wave discharges in chronic epilepsy. Calcium ions trigger the synthesis of cAMP (Kuisle et al., 2006).
	Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and acquired temporal lobe epilepsy model (Smith and Delisle, 2015)	Absence seizure and status epilepticus (Smith and Delisle, 2015)	Diminished cardiac expression of HCN2 in both models. Chronic epilepsy can induce cardiac channelopathies thus SUDEP (Smith and Delisle, 2015)
	Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and acquired temporal lobe epilepsy (Powell et al., 2014)	Post–status epilepticus (Powell et al., 2014)	Secondary ion channelopathies and cardiac dysfunction can result from the chronic epilepsy (Powell et al., 2014)
	Genetic Absence Epilepsy Rats from Strasbourg (GAERS), male Wistar rats, male Stargazer mice (David et al., 2018)	Absence seizures (David et al., 2018)	Blockage of HCN channels via ZD7288 antagonist in ventrobasal thalamus decreases thalamocortical neuron firing and eliminates spontaneous absence seizures in GAERS, Wistar rats and male Stargazer mice (David et al., 2018).
	Wistar Albino Glaxo rats, bred in Rijswijk (Budde et al., 2005)	Absence epilepsy (Budde et al., 2005)	There is a need of the balance of HCN1 and HCN2 gene expression in thalamocortical for the modulation of burst firing in thalamic networks (spindle-like or spike-wave-like patterns). Increased expression of HCN1 and no changes for the rest of HCN channels (Budde et al., 2005).
	Rat Pilocarpine Model of Epilepsy (Jung et al., 2007)	Spontaneous induced recurrent seizures (Jung et al., 2007)	The diminished expression of the dendritic HCN channels during the acute phase of the epilepsy is accompanied by the loss of hyperpolarization of voltage-dependent activation. These phenomena progressed to the chronic phase which increases neuronal excitability and thus epileptogenesis. Phenobarbital could suppress seizures and reversed the current changes but not the expression (Jung et al., 2007).
	Rat Pilocarpine Model of Epilepsy (Jung et al., 2011)	Spontaneous induced recurrent seizures (Jung et al., 2011)	Loss Ih current and HCN1channel expression start 1 h after status epilepticus and involves several steps including dendritic HCN1 channel internalization, deferred loss of protein expression, and finally the downregulation of mRNA expression (Jung et al., 2011).
	Wistar Albino Glaxo/Rij strain (Wemhöner et al., 2015)	Absence epilepsy (Wemhöner et al., 2015)	Gain-of-function of WAG-HCN1is caused by N-terminal deletion, increase of the HCN1expression and current, suppression of HCN2 and HCN4 currents as well as reduction of cAMP sensitivity (Wemhöner et al., 2015).
	Tottering mice (Kase et al., 2012)	Absence seizures (Kase et al., 2012)	Reduction of HCN function which led to enhancement of membrane excitability in subthalamic nucleus neurons. The activation of HCN channel activity in vitro could rescue the situation (Kase et al., 2012).

KO, knockout.