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.