GABAA receptor function is enhanced by Interleukin-10 in human epileptogenic gangliogliomas and its effect is counteracted by Interleukin-1β

Abstract

Gangliogliomas (GGs) are low-grade brain tumours that cause intractable focal epilepsy in children and adults. In GG, as in epileptogenic focal malformations (i.e., tuberous sclerosis complex, TSC), there is evidence of sustained neuroinflammation with involvement of the pro-inflammatory cytokine IL-1β. On the other hand, anti-inflammatory mediators are less studied but bear relevance for understanding seizure mechanisms. Therefore, we investigated the effect of the key anti-inflammatory cytokine IL-10 on GABAergic neurotransmission in GG. We assessed the IL-10 dependent signaling by transcriptomic analysis, immunohistochemistry and performed voltage-clamp recordings on Xenopus oocytes microtransplanted with cell membranes from brain specimens, to overcome the limited availability of acute GG slices. We report that IL-10-related mRNAs were up-regulated in GG and slightly in TSC. Moreover, we found IL-10 receptors are expressed by neurons and astroglia. Furthermore, GABA currents were potentiated significantly by IL-10 in GG. This effect was time and dose-dependent and inhibited by blockade of IL-10 signaling. Notably, in the same tissue, IL-1β reduced GABA current amplitude and prevented the IL-10 effect. These results suggest that in epileptogenic tissue, pro-inflammatory mechanisms of hyperexcitability prevail over key anti-inflammatory pathways enhancing GABAergic inhibition. Hence, boosting the effects of specific anti-inflammatory molecules could resolve inflammation and reduce intractable seizures.

Immune Mechanisms in Epileptogenesis: Update on Diagnosis and Treatment of Autoimmune Epilepsy Syndromes

“…While short-term exposure of neurons to IL-1β leads to a reduction of voltage-gated sodium currents, longer exposure (hours or days) results in a marked increase and can cause hyperexcitability [ 77 ]. The same, time-dependent effects of IL-1β are observed on GABA-A receptor mediated currents in ganglioglioma [ 78 ]. It also has been shown that IL-1β enhances expression of NMDA receptor subtype 2B leading to an increased Ca 2+ influx and hyperexcitability.…”

Unraveling the links between circulating bioactive factors and epilepsy: A bidirectional Mendelian randomization study

“…Notably, IL-1β decreases GABA currents’ amplitude and impedes the efficacy of IL-10. [50] Focal epilepsy is believed to elevate IL-10 as a possible safeguarding mechanism in the brain that mitigates inflammatory harm. It is noted that IL-10 secretion is subject to seizure frequency and depletes with the progression of the disease.…”

Getting Excited About Chloride Cotransporters: Neuroinflammation and Inhibition

“…Based on the findings of this paper, prevention of NKCC1/KCC2-mediated changes in chloride conductance would diminish the loss of GABAergic inhibition, although an alternative explanation is that protective effects of anti-inflammatory cytokines contribute to the sparing of GABAergic inhibition in the face of neuroinflammatory insults. 8 Like other potential mechanisms, these hypotheses need to be evaluated more firmly in order to understand the causative relationship of inhibition (post-synaptic Cl − regulatory and/or presynaptic interneuronal GABA release mechanisms 9 ) in neuroinflammation and hyperexcitability/seizures. Curiously, BDNF and its inhibition (as discussed earlier) may be an important mechanism of reducing the impact of inflammation on chloride cotransporters.…”