5.3 What is the cellular and molecular mechanism of histaminergic system in epilepsy?
The imbalance of excitatory glutamatergic and inhibitory GABAergic neurons is considered as the classical theory for epilepsy. The action of histamine is localized in histaminergic neurons or innervating to glutamatergic or GABAergic neurons which is not fully understood. The well development of transgenic mice, such as HDC-Cre, CamKIIα-Cre, and Vgat-Cre are available to neuronal specific modulation with the help of optogenetic. H3R acts as heteroreceptor which regulates other neurotransmitters synthesis and release. In the cultured cortical neurons, the H3R antagonist clobenopropit effectively reduced the NMDA-induced neuronal toxicity by increasing GABA releases through cAMP/PKA signaling pathway (Dai et al., 2007).Whether other neurotransmitters, such as glutamate, GABA, acetylcholine and 5-HT participating in the action of H3R needs to identify further. Voltage-gated ion channels including Na+, Ca2+ and K+ channels, contribute to the generation of seizure discharges (Catterall, 2014; van Loo et al., 2019; Wei et al., 2017; Yuan & Isom, 2014). Whether histamine or its receptor regulate voltage-gated ion channels activity in epilepsy needs further evaluation. Since cellular single RNA sequencing with high efficiency (Lein, Borm & Linnarsson, 2017), that provides a convenient way to investigate the molecular mechanism.
In conclusion, plenty of evidence suggested the histamine and its receptor are involved in epilepsy. The discovery of the central histaminergic system broadens the AED development aspects, especially for H3R antagonists. Nevertheless, there are many questions unsolved. A precise understanding of the role of the central histaminergic system in epilepsy at molecular, cellular, or even neural circuit level is encouraged to clinical transformation in epilepsy therapeutics.