Downregulation of astrocytic K_ir channels has indeed been found in the injured or diseased CNS. K_ir currents are reduced following injury-induced reactive gliosis in vitro [59], entorhinal cortex lesion [60], freeze lesion-induced cortical dysplasia [61,62], and traumatic [63] and ischemic [64] brain injury. In addition, human tissue studies have reported a significant loss of perivascular K_ir4.1 expression (~50%) and function in TLE patients, suggesting impaired spatial K⁺ buffering in the epileptic hippocampus [65–71]. Reduction in K_ir conductance in astrocytes [69] and potassium clearance [71] were observed in human epilepsy specimens. Interestingly, two studies directly examined astrocytic K⁺ currents in sclerotic versus nonsclerotic hippocampi resected from epileptic patients. Using ion-sensitive microelectrodes, Heinemann’s group compared glial Ba²⁺-sensitive K⁺ uptake in the CA1 region of hippocampal slices obtained from patients with or without mesial temporal sclerosis [68,72]. Ba²⁺, a blocker of K_ir channels, augmented stimulus-evoked K⁺ elevation in nonsclerotic but not in sclerotic specimens, suggesting an impairment in K_ir-mediated K⁺ buffering in sclerotic tissue. Direct evidence for downregulation of K_ir currents in the sclerotic CA1 region of hippocampus came from Steinhäuser’s group who found, using comparative patch-clamp analysis, that there was a reduction in astroglial K_ir currents in sclerotic compared to nonsclerotic hippocampi [67]. These data indicate that dysfunction of astroglial K_ir channels could underlie impaired K⁺ buffering and contribute to hyperexcitability in epileptic tissue [73]. More recently, Heuser et al. found that the loss of astrocytic K_ir4.1 expression was most pronounced around vessels in gliotic areas of the sclerotic hippocampus of mesial temporal lobe epilepsy (MTLE) patients [66]. Thus, increasing evidence suggests that the dysregulation of K⁺ spatial buffering may play a role in hyperexcitability. Direct evidence for a potential causative role of reduced K_ir4.1 channel expression in epileptogenesis derives from an albumin model of BBB disruption in which K_ir4.1 downregulation occurs prior to onset of epilepsy; [74,75] however, other studies report no changes in astrocytic K_ir currents 7–16 days following systemic kainic acid injection [76] and increased K_ir4.1 expression in a rat pilocarpine model [77]. K_ir4.1 may also be regulated by inflammatory cytokines such as interleukin (IL)-1β [78] which are known to play a role in epilepsy (see Chapter 13: Inflammation).

Further evidence for a role of alteration in K_ir4.1 function in human epilepsy arises from genetic association studies. Quantitative trait loci mapping in mice led to identification of genetic variation in the K_ir4.1 gene Kcnj10; this led to human genetic association studies which identified an association between the human K_ir4.1 gene KCNJ10 mutations and seizure susceptibility in human populations [79,80]. Further evidence was adduced for an allelic association with variations in KCNJ10 and idiopathic generalized epilepsy [81,82]. Interestingly, human subjects were subsequently found with homozygous loss-of-function mutations in KCNJ10 leading to the definition of a specific autosomal recessive syndrome consisting of Epilepsy, Ataxia, Sensorineural deafness, and Tubulopathy (EAST syndrome) [83,84], a different version of which was also termed SeSAME syndrome (Seizures, Sensorineural deafness, Ataxia, Mental retardation, and Electrolyte imbalance) [85], both together termed SeSAME/EAST syndrome [86]. The combined phenotype of this syndrome parallels well the expression of K_ir4.1 in the brain, inner ear, and kidney. A subset of patients with autism and epilepsy were found to have gain-of-function mutations of KCNJ10 [87]. Single nucleotide variations in the KCNJ10 gene have also been found in TLE patients with hippocampal sclerosis [88].

It is important to recognize that aside from K_ir4.1/KCNJ10, a wide variety of mutations in K⁺ channels have been described in distinct forms of animal and human epilepsies [89] (Tables 7.2 and 7.3). However, as most K⁺ channels are not specific to astrocytes and are also expressed by neurons, a detailed discussion of each of these K⁺ channel mutations and syndromes is beyond the scope of this chapter and is not pathophysiologically limited to astrocytes. K_ir4.1/KCNJ10 mutations represent a “purer” astrocytic contribution to epilepsy. Nevertheless, it is instructive to note the powerful impact of K⁺ channel mutations—both neuronal and astrocytic—have on excitability and seizure susceptibility. In the case of K_ir4.1 loss-of-function mutations, seizure susceptibility likely arises from abrogation of the K⁺ buffering mechanisms described above; whereas in the case of K_v channel mutations in neurons, seizure susceptibility is likely more related to loss of neuronal repolarization [90]. Interestingly, one of the newest and most promising antiepileptic drug mechanisms of action is that of retigabine, which activates voltage-dependent K⁺ channels of the K_v7 subfamily and is thus a “neuronal potassium channel opener” [91]. No similar drug yet exists to activate glial K_ir channels.

Table 7.2

K⁺ Channelopathies in Human Epilepsies

Channel	Gene/Protein	Expression in Brain Regions Relevant to Epilepsy	Epilepsy Type	Gene Mutation/Channel Dysfunction	References
Voltage-gated K+ channels	KCNA1/Kv1.1 (pore forming α subunit)	Axons/terminals of hippocampal neurons (Shaffer collateral axons and mossy fibers contacting CA3 neurons); hippocampal interneurons of hilus and CA1; neocortical pyramidal neurons	Generalized and partial seizures associated to EA1	Loss-of-function mutations generally associated with reduced current amplitudes; positive shift of the activation V1/2; increased sensitivity to Zn2+ inhibition	Assaf and Chung (1984); Browne et al. (1994); Adelman et al. (1995); D’Adamo et al. (1998, 1999); Zuberi et al. (1999); Geiger and Jonas (2000); Cusimano et al. (2004); Imbrici et al. (2006, 2007, 2008); Guan et al. (2006)
	KCNAB2/Kvβ2 (β accessory subunit for Kv1 channels)	Widely expressed in cerebral cortex and hippocampus	Severe epilepsy including infantil spasms	Allele diletion/haploinsufficiency	Heilstedt et al. (2001)
	LGI1 (accessory protein for Kv1 channels)	Neocortex and hippocampus	Autosomal dominant lateral temporal lobe epilepsy	E383A, frameshift with protein truncation/Mutated LGI1 does not prevent Kvβ1-mediated Kv1 channel inactivation, a function performed by the WT protein	Kalachikov et al. (2002); Morante-Redolat et al. (2002)
	KCND2/Kv4.2 (IA pore forming α subunit)	Dentrites of hippocampal neurons	Temporal lobe epilepsy	Truncated Kv4.2 subunit/attenuated IA current density	Singh et al. (2006)
	KCNV2/Kv8.2 (silent subunit associating with Kv2 channels)	Pyramidal neurons and principal excitatory neurons of the pyramidal cell layers and the dentate gyrus; cortex, with high levels of transcript in layers 2/3 and 5	Febrile and afebrile partial seizures; epileptic encephalopathy	R7K, M285K/Reduction of Kv2.1 mediated current; M285K impairs the voltage-dependence of the channel	Jorge et al. (2011)
	KCNQ2-3/Kv7.2-3 (M current pore forming α subunit)	Widely expressed in brain at neuronal cell bodies	Benign familial neonatal convulsions	Five-base pair insertion deleting more than 300 amino acids from the KCNQ2; missense mutations in critical regions for KCNQ3 channel function / Reduced KCNQ current amplitudes	Biervert et al. (1998); Charlier et al. (1998); Schroder et al. (1998); Singh et al. (1998)
	KCNH2/Kv11.2 (HERG channel pore forming α subunit)	Widely expressed in brain	Epilepsy associated with type 2 long QT syndrome	Loss-of-function mutations	Keller et al. (2009); Omichi et al. (2010); Tu et al. (2011); Zamorano-León et al. (2012)
Ca2+-dependent K+ channels	KCNMA1/KCa1.1 (BK channel pore forming α subunit)	Axons and presynaptic terminals of excitatory neurons of cortex and hippocampus	Generalized epilepsy and paroxysmal diskynesia	D434G/Increase of channel open probability and calcium dependence of KCa1.1 expressed alone or with KCaβ1, KCaβ2, or KCaβ4; loss-of-function of KCa1.1/KCaβ3-mediated currents	Du et al. (2005); Díez-Sampedro et al. (2006); Lee and Cui (2009); Yang et al. (2010)
	KCNMB3/KCaβ3 (accessory protein for KCa1.1 channels)	Widely expressed at low levels in brain	Idiopathic generalized epilepsy	Loss-of-function of KCa1.1/KCaβ3-mediated currents	Behrens et al. (2000); Hu et al. (2003); Lorenz et al. (2007)
Inwardly rectifying K+ channels	KCNJ2/Kir2.1 (pore forming α subunit)	Hippocampus, caudate, putamen, nucleus accumbens; to lower levels in habenula and amygdale	Seizures associated to the Andersen Tawil Syndrome (ATS)	Loss-of-function mutations with dominant-negative effects	Haruna et al. (2007); Chan et al. (2010)
	KCNJ10/Kir4.1 (pore forming α subunit)	Oligodendrocytes and astrocytes surrounding synapses and blood vessels, mainly in the cortex, thalamus, hippocampus, and brainstem	Seizure susceptibility	R271C missense variation; no alteration in the biophysical properties of the channel when heterologously expressed	Buono et al. (2004); Connors et al. (2004); Shang et al. (2005)
			Epilepsy associated to EAST syndrome	Loss-of-function recessive mutations	Bockenhauer et al. (2009); Scholl et al. (2009)
			Epilepsy associated to autism spectrum disorders (ASDs)	R18Q, V84M, gain-of-function of Kir4.1 and Kir4.1/Kir5.1-mediated current	Sicca et al. (2011)
	KCNJ11/Kir6.2 (KATP channel pore forming α subunit)	Hippocampus (principal neurons, interneurons, and glial cells); neocortex, entorhinal, and piriform cortex	Developmental delay, epilepsy, and neonatal diabetes mellitus (DEND syndrome)	Gain-of-function mutations leading to decreased channel inhibition by ATP, or enhanced Mg2+-nucleotide-induced activation	Karschin et al. (1997); Hattersley and Ashcroft (2005)
	ABCC8/SUR1 (KATP channel accessory regulatory subunit)

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