Bidirectional regulation of glial potassium buffering – glioprotection versus neuroprotection

Abstract

Glia modulate neuronal excitability and seizure sensitivity by maintaining potassium and water homeostasis. A SIK3-regulated gene expression program controls the glial capacity to buffer K+ and water in Drosophila, however upstream regulatory mechanisms are unknown. Here we identify an octopaminergic circuit linking neuronal activity to glial ion and water buffering. Under basal conditions, octopamine functions through the inhibitory octopaminergic GPCR OctbR to upregulate glial buffering capacity, while under pathological K+ stress, octopamine signals through the stimulatory octopaminergic GPCR OAMB1 to downregulate the glial buffering program. Failure to downregulate this program leads to intracellular glia swelling and stress signaling, suggesting that turning down this pathway is glioprotective. In the eag shaker Drosophila seizure model, the SIK3-mediated buffering pathway in inactivated. Re-activation of the glial buffering program dramatically suppresses neuronal hyperactivity, seizures, and shortened lifespan in this mutant. These findings highlight the therapeutic potential of a glial-centric therapeutic strategy for diseases of hyperexcitability.

SIK3 and Wnk converge on Fray to regulate glial K+ buffering and seizure susceptibility

“…In contrast, there is no difference between the HDAC4 nuclear to cytoplasmic ratio in the Sei TS1 or NCKX zyd as compared to control flies, suggesting the SIK3 glial K + buffering program is unaffected by these mutants in these glia. In conjunction with our prior findings that the SIK3 K + buffering program is turned off in eag shaker double mutants [ 14 ], these data show that neuronal excitability inhibits glial K + buffering in some, but not all, glial cells in some seizure mutants.…”

“…The SIK3/HDAC4 glial K + buffering program is inhibited in eag shaker , a double mutant for the ERG and Shaker-type K + channels [ 14 ]. Inhibition of this program occurs via shuttling of HDAC4 to nucleus, and can lead to peripheral nerve edema that is observed as nerve swellings.…”

“…In our previous study, we made the surprising observation that the SIK3 glial ionic buffering program is inactivated in eag Shaker , a classic seizure mutant [ 14 ]. We provided evidence that the program is turned off by glia for self-protection, as re-activating this program induces glial cell swelling and activates JNK, a central cell stress signaling pathway.…”

“…However, turning off the glial SIK3 program comes at the cost of exacerbating neuronal hyperexcitability. Indeed, reactivation of the SIK3 glial ionic buffering program is sufficient to suppress seizure behavior and dramatically extend lifespan in the eag Shaker mutant [ 14 ]. Here we investigated whether this glioprotective inactivation of K + buffering was a peculiarity of the eag Shaker mutant, or a more general feature of hyperexcitability mutants.…”

“…Loss of SIK3 in glia disrupts K+ buffering and leads to neuronal hyperexcitability and nerve edema, highlighting the key role SIK3 plays in water/ion homeostasis for the nervous system. Interestingly, we demonstrated in the Drosophila seizure model Eag Shaker , a double mutant for both ERG and Shaker-type K + channels, that the glial SIK3-HDAC4 pathway is inactivated and re-activation of the glial SIK3-HDAC4 pathway suppresses seizure behavior and significantly extends lifespan [ 14 ]. The dramatic seizure suppression observed in Eag Shaker motivated us to explore whether bolstering the glial capacity to buffer K + could also suppress seizure behavior in molecularly distinct seizure mutants.…”