**5. Transient receptor potential channels**

Transient receptor potential (TRP) channels, which could induce a transient voltage changes to continuous light mutations of *Drosophila melanogaster*, are expressed in photoreceptors carrying trp gene. The first homologous human gene was reported in 1995. There are 30 trp genes, and more than 100 TRP channels have been identified so far, and TRP channels were divided into 7 subfamilies, including TRPC, TRPV, TRPM, TRPA, TRPP, TRPML, and TRPN. Focus on TRPs, one family of Ca2+ channels, plays a role in neuronal excitability. It is obviously known that Ca2+ is an important second messenger, which is related to the etiology of epilepsy [101]. Therefore, TRP channels are thought to be partially responsible for epileptic seizures, especially for TPRC and TRPV1 channels.

### **5.1 Canonical transient receptor potential (TRPC)**

TRPC channels are the closet homolog to Drosophila TRP channels. Based on the functional comparisons and sequence alignments, four subsets of mammalian TRPCs (TRPC1, TRPC2, TRPC3/6/7, and TRPC4/5) have been generated [101]. These channels form receptor-modulated currents in the mammalian brain and important to SE-induced neuronal cell death. These channels could play a critical role in the generation of spontaneous seizures. TRPC1 and TRPC4 are expressed in CA1 pyramidal neurons. The amplitude of the plateau and the number of spikes

**181**

*Ion Channels in Epilepsy: Blasting Fuse for Neuronal Hyperexcitability*

**5.2 Transient receptor potential vanilloid 1 (TRPV1)**

were significantly reduced in mice without TRPC1 and TRPC4 [102]. TRPC3 channels are found to be responsible for pilocarpine-induced status epilepticus (SE) in mice. The reduction on SE in TRPC3 KO mice is caused by a selective attenuation of pilocarpine-induced theta wave activity [103]. TRPC7 can be detected in CA3 pyramidal neurons largely. The spontaneous seizures in CA3 pyramidal neurons and the pilocarpine-induced increase in gamma wave activities during the latent

TRPV1 is one subfamily of TRP channels, expressing in most neurons. The expression of TRPV1 protein in epileptic brain areas was increased [105], but the epileptic activity in hippocampal slices was decreased by iodoresiniferatoxin (IRTX), a selective TRPV1 channel antagonist [106]. It is well known that glutamate could be released when the TRPV1 channel was activated [107], and the glutamate neurotransmitters are related to the etiology of epilepsy. Thus, focusing the TRPV1 channels activity may be important for the modulating neuronal excitability in epilepsy [106]. Recent studies showed that the high expression of TRPV1 channels could induce the temporal lobe epilepsy [105]. Cytosolic calcium elevation through activation of TRPV1 channels plays a physiologically relevant role in the regulation of epileptic seizures [108], decreasing the calcium accumulation by inhibiting the TRPV1 channels, could play a neuronal protective role against epilepsy-induced Ca2+ entry in hippocampal neurons. As mentioned above, the TRPV1 could be activated by hyperthermia; the hyperthermia-induced TRPV1 might be an effective candidate therapeutic target in heat-induced hyperexcitation [109, 110]. The activation of TRPV1 promotes glutamate release by increasing the excitability of neurons and synaptic terminals [111]. Whereas the activities would be reduced in hippocampus slices of rats after given the CPZ and ITRX, which were the TRPV1 channel blockers.

At present, the treatment of epilepsy is still dominated by drugs. More than 35% of marketed antiepileptic drugs target VGICs, such as phenytoin, carbamazepine, oxcarbazepine, and ethosuximide. Phenytoin and carbamazepine are broad-spectrum antiepileptic drugs blocking VGSCs as their primary mechanism of action. For example, phenytoin is a more effective inhibitor of SCN8A-I1327V than other drugs [112], which could be used in treating patients with gain-of-function mutations of SCN8A. Different types of VGCCs play different roles in the pathological process of epilepsy. Decreased expression of P/Q type could induce epilepsy, whereas increased expression of N-type and T-type calcium channels could lead to epilepsy. Calcium blockers including ethosuximide have been widely accepted for the treatment of absence epilepsy [71]. Gain-of-function BK channels contribute to epileptogenesis and seizure generation. BK-blocking agents, like paxilline [49], might be used as potential therapeutic drugs. In the future, novel techniques might contribute to develop reasonable therapies for treating inherited or acquired epileptic syndromes. For instance, induced pluripotent stem cells (IPS) and genetically engineering animal models could be used for accurate treatments of epilepsy. Single-nucleotide polymorphisms (SNPs) of VGIC genes from hereditary epilepsy patients could be detected by *de novo* genomic sequencing. VGICs of IPS cells could be mutated by CRISPR-Cas9 according to the information of these SNPs [113]. Through inducing IPS cells differentiated into neurons, phenotype of VGIC gene SNPs could be well investigated. It is also a well-detection platform for selecting antiepileptic drugs that would be sensitive to mutated VGICs *in vitro* [112]. For *in vivo*

period could be significantly reduced by ablating the gene TRPC7 [104].

*DOI: http://dx.doi.org/10.5772/intechopen.83698*

**6. Antiepileptic therapy and beyond**

*Ion Channels in Epilepsy: Blasting Fuse for Neuronal Hyperexcitability DOI: http://dx.doi.org/10.5772/intechopen.83698*

*Epilepsy - Advances in Diagnosis and Therapy*

mice compared with controls. It indicated that the

mice display

mice [97]. Cav3.2

mice are resistant to SWD

Cav2.3 plays a crucial role in both hippocampal ictogenesis and seizure generalization and is of central importance in neuronal degeneration after excitotoxic events [89].

T-type channels, widely distributed in the thalamus, are important for the repetitive firing of APs in rhythmically firing cells, which could be activated and inactivated more rapidly at more negative membrane potentials than other VGCCs [90]. Three subtypes of T-type channels have been identified, designated as Cav3.1, Cav3.2, and Cav3.3; they correspond to complexes containing the pore-forming α1 subunits, α1G, α1H, and α1I, respectively [91]. It has long been suggested that generalized absence seizures are accompanied by hyperexcitable oscillatory activities in the thalamocortical network [92]. The evidence that succinimide and related anticonvulsants could block thalamic T-type channels make researchers speculate that T-type Ca2+ channels might be related to the pathogenesis of spike-and-wave discharges (SWDs) in gen-

significantly reduced duration of seizures compared to wild type, but the frequency of seizures increased slightly [94]. In the WAG/Rij model, the expression of Cav3.1 may be related to age, and blocking Cav3.1 can reduce the onset of epilepsy [94, 95] which suggested that decrease in Cav3.1 channel expression and Ca2+ current component that they carry in thalamocortical relay neurons serves as a protective measure against early

seizures specifically induced by γ-GABABR agonists. Simultaneously, the γ-GABABR

single nucleotide mutation has been reported in patients with childhood absence epilepsy and other types of idiopathic generalized epilepsies [98, 99]. Gain-of-function mutations (C456S) in Cav3.2 channels increase seizure susceptibility by directly altering neuronal electrical properties and indirectly by changing gene expression [100].

Transient receptor potential (TRP) channels, which could induce a transient voltage changes to continuous light mutations of *Drosophila melanogaster*, are expressed in photoreceptors carrying trp gene. The first homologous human gene was reported in 1995. There are 30 trp genes, and more than 100 TRP channels have been identified so far, and TRP channels were divided into 7 subfamilies, including TRPC, TRPV, TRPM, TRPA, TRPP, TRPML, and TRPN. Focus on TRPs, one family of Ca2+ channels, plays a role in neuronal excitability. It is obviously known that Ca2+ is an important second messenger, which is related to the etiology of epilepsy [101]. Therefore, TRP channels are thought to be partially responsible for epileptic

TRPC channels are the closet homolog to Drosophila TRP channels. Based on the functional comparisons and sequence alignments, four subsets of mammalian TRPCs (TRPC1, TRPC2, TRPC3/6/7, and TRPC4/5) have been generated [101]. These channels form receptor-modulated currents in the mammalian brain and important to SE-induced neuronal cell death. These channels could play a critical role in the generation of spontaneous seizures. TRPC1 and TRPC4 are expressed in CA1 pyramidal neurons. The amplitude of the plateau and the number of spikes

eralized absence seizures [93]. In the kainate epilepsy model, Cav3.1<sup>−</sup>/<sup>−</sup>

agonists induced only very weak and intermittent SWDs in Cav3.1<sup>−</sup>/<sup>−</sup>

onset of SWD and absence seizures [96]. Notably, Cav3.1<sup>−</sup>/<sup>−</sup>

**5. Transient receptor potential channels**

seizures, especially for TPRC and TRPV1 channels.

**5.1 Canonical transient receptor potential (TRPC)**

and excitotoxic effects in Cav2.3<sup>−</sup>/<sup>−</sup>

**4.3 T-type Cav**

**180**

were significantly reduced in mice without TRPC1 and TRPC4 [102]. TRPC3 channels are found to be responsible for pilocarpine-induced status epilepticus (SE) in mice. The reduction on SE in TRPC3 KO mice is caused by a selective attenuation of pilocarpine-induced theta wave activity [103]. TRPC7 can be detected in CA3 pyramidal neurons largely. The spontaneous seizures in CA3 pyramidal neurons and the pilocarpine-induced increase in gamma wave activities during the latent period could be significantly reduced by ablating the gene TRPC7 [104].

## **5.2 Transient receptor potential vanilloid 1 (TRPV1)**

TRPV1 is one subfamily of TRP channels, expressing in most neurons. The expression of TRPV1 protein in epileptic brain areas was increased [105], but the epileptic activity in hippocampal slices was decreased by iodoresiniferatoxin (IRTX), a selective TRPV1 channel antagonist [106]. It is well known that glutamate could be released when the TRPV1 channel was activated [107], and the glutamate neurotransmitters are related to the etiology of epilepsy. Thus, focusing the TRPV1 channels activity may be important for the modulating neuronal excitability in epilepsy [106]. Recent studies showed that the high expression of TRPV1 channels could induce the temporal lobe epilepsy [105]. Cytosolic calcium elevation through activation of TRPV1 channels plays a physiologically relevant role in the regulation of epileptic seizures [108], decreasing the calcium accumulation by inhibiting the TRPV1 channels, could play a neuronal protective role against epilepsy-induced Ca2+ entry in hippocampal neurons. As mentioned above, the TRPV1 could be activated by hyperthermia; the hyperthermia-induced TRPV1 might be an effective candidate therapeutic target in heat-induced hyperexcitation [109, 110]. The activation of TRPV1 promotes glutamate release by increasing the excitability of neurons and synaptic terminals [111]. Whereas the activities would be reduced in hippocampus slices of rats after given the CPZ and ITRX, which were the TRPV1 channel blockers.
