Astrocytic Acid-Sensing Ion Channel 1a Contributes to the Development of Chronic Epileptogenesis

Abstract

Unraveling mechanisms underlying epileptogenesis after brain injury is an unmet medical challenge. Although histopathological studies have revealed that reactive astrogliosis and tissue acidosis are prominent features in epileptogenic foci, their roles in epileptogenesis remain unclear. Here, we explored whether astrocytic acid-sensing ion channel-1a (ASIC1a) contributes to the development of chronic epilepsy. High levels of ASIC1a were measured in reactive astrocytes in the hippocampi of patients with temporal lobe epilepsy (TLE) and epileptic mice. Extracellular acidosis caused a significant Ca2+ influx in cultured astrocytes, and this influx was sensitive to inhibition by the ASIC1a-specific blocker psalmotoxin 1 (PcTX1). In addition, recombinant adeno-associated virus (rAAV) vectors carrying a GFAP promoter in conjunction with ASIC1a shRNA or cDNA were generated to suppress or restore, respectively, ASIC1a expression in astrocytes. Injection of rAAV-ASIC1a-shRNA into the dentate gyrus of the wide type TLE mouse model resulted in the inhibition of astrocytic ASIC1a expression and a reduction in spontaneous seizures. By contrast, rAAV-ASIC1a-cDNA restored astrocytic ASIC1a expression in an ASIC1a knock-out TLE mouse model and increased the frequency of spontaneous seizures. Taken together, our results reveal that astrocytic ASIC1a may be an attractive new target for the treatment of epilepsy.

Disruption of auto-inhibition underlies conformational signaling of ASIC1a to induce neuronal necroptosis

“…Upon decrease in extracellular pH, ASIC1a is activated to produce a transient inward current mediated mainly by Na + , with a small component of Ca 2+ 1,7-9 . Traditionally, the Ca 2+ influx is thought to cause cytosolic Ca 2+ overload and thereby acidotoxicity 1,[7][8][9] . However, we recently uncovered that the ion conducting function of ASIC1a is not required for the extracellular acid-induced neuronal cell demise 2 .…”

“…Disruption of this autoinhibition underlies conformational signaling of ASIC1a to induce neuronal necroptosis. Testing synthetic membranepenetrating peptides representing the distal NT of ASIC1a, we identify peptide NT [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] to offer protection to neurons in both acidosis-induced necroptosis in vitro and a mouse model of ischemic stroke in vivo, providing proof of concept for a neuroprotective strategy against acidotoxicity.…”

ASIC1A in neurons is critical for fear‐related behaviors

“…; Yang et al . ) and may contribute to acid‐evoked currents and calcium influx in astrocytes (Huang et al . ; Yang et al .…”

“…; Yang et al . ), although relative levels of ASIC1A expression in neurons and nonneuronal cells remain unclear. Most of the tools previously used to manipulate ASIC1A have not discriminated between neuronal and nonneuronal cells.…”

“…ASIC1A is expressed in neurons and has been located in the soma, axons, dendrites and dendritic spines, where it has been implicated in synaptic transmission and plasticity (Wemmie et al 2002;Zha et al 2006;Zha et al 2009;Du et al 2014;Kreple et al 2014). However, recent studies have suggested that ASICs might also be present in subpopulations of glial cells Feldman et al 2008;Lin et al 2010;Yang et al 2016) and may contribute to acid-evoked currents and calcium influx in astrocytes Yang et al 2016), although relative levels of ASIC1A expression in neurons and nonneuronal cells remain unclear. Most of the tools previously used to manipulate ASIC1A have not discriminated between neuronal and nonneuronal cells.…”