Regulation of chemoconvulsant‐induced seizures by store‐operated Orai1 channels

Abstract

Temporal lobe epilepsy is a complex neurological disease caused by imbalance of excitation and inhibition in the brain. Growing literature implicates altered Ca 2+ signalling in many aspects of epilepsy but the diversity of Ca 2+ channels that regulate this syndrome are not well-understood. r Here, we report that mice lacking the store-operated Ca 2+ channel, Orai1, in the brain show markedly stronger seizures in response to the chemoconvulsants, kainic acid and pilocarpine. r Electrophysiological analysis reveals that selective deletion of Orai1 channels in inhibitory neurons disables chemoconvulsant-induced excitation of GABAergic neurons in the CA1 hippocampus. r Likewise, deletion of Orai1 in GABAergic neurons abrogates the chemoconvulsant-induced burst of spontaneous inhibitory postsynaptic currents (sIPSCs) on CA1 pyramidal neurons in the hippocampus. This loss of chemoconvulsant inhibition likely aggravates status epilepticus in Orai1 KO mice. r These results identify Orai1 channels as regulators of hippocampal interneuron excitability and seizures.

Orai1 Channels Are Essential for Amplification of Glutamate-Evoked Ca2+ Signals in Dendritic Spines to Regulate Working and Associative Memory

“…To address this question, we next examined behavioral learning in excitatory neuron-specific Orai1 KO (Orai1 fl/fl CaMKIIa-Cre ) mice. As a comparison, we also studied mice lacking Orai1 only in inhibitory neurons (Orai1 fl/fl Gad2-Cre mice) ( Hori et al, 2020 ).…”

“…Tissue-specific deletion of Orai1 in the brain was accomplished as previously described ( Hori et al, 2020 ; Somasundaram et al, 2014 ; Toth et al, 2019 ). Briefly, Orai1 fl/fl mice (provided by Amgen Inc.) and Orai1 fl/+ were crossed with nestin-Cre mice (003771 from The Jackson Laboratory) to generate Orai1 fl/fl Nes-Cre (brain-specific KO) and Orai1 fl/+ Nes-Cre (brain-specific heterozygote).…”

“…To delete Orai1 selectively in excitatory (glutamatergic) neurons of the forebrain, Orai1 fl/fl mice were crossed with Camk2a-Cre mice (005359 from the Jackson Laboratory) ( Tsien, 1998 ; Tsien et al, 1996 ) to yield Orai1 fl/fl CaMKIIa-Cre mice. Deletion in inhibitory interneurons was achieved by crossing Orai1 fl/fl mice with Gad2-Cre mice (010802 from the Jackson Laboratory) ( Taniguchi et al, 2011 ) as previously described ( Hori et al, 2020 ).…”

“…For example, in neural progenitor cells, astrocytes, and microglia, Ca 2+ influx through Orai1 regulates gene expression, gliotransmitter release, and the generation of inflammatory mediators ( Deb et al, 2020 ; Gao et al, 2016 ; Heo et al, 2015 ; Somasundaram et al, 2014 ; Toth et al, 2019 ). Additionally, in spinal nociceptive neurons and hippocampal interneurons, Orai1 mediates SOCE and is implicated in the regulation of chronic pain and seizure-like activity ( Dou et al, 2018 ; Hori et al, 2020 ; Majewski et al, 2019 ). By contrast, we know comparatively little about the role of Orai1 channels for Ca 2+ signaling and effector functions in excitatory neurons.…”

Regulation of neuropathic pain by microglial Orai1 channels

“…5A) . The SG region of the dorsal horn was visually identified in spinal cord slices with a water immersion objective, and sEPSCs were recorded from SG neurons in the whole-cell patch-clamp mode at -70 mV in the presence of GABA and NMDAR blockers as described previously ( 43 , 77 ).…”