Now We Can Tame the Wild West of Controlling Astrocytes for Treating Neocortical Epilepsy

Are activated astrocytes pro-excitatory in epilepsy? The answer tends to be “yes” with cumulative evidence proposing that astrocytic activation leads to hyperexcitability through excitatory transmitter release or neuroinflammatory pathways [1–3]. But a very recent study published in Nature Communications by Zhao J et al. has refreshed this viewpoint by showing that optogenetic activation of astrocytes can alleviate neocortical seizures (a type of epileptic symptom that originates in the neocortex which is part of the external surface layer of the brain) through astrocytic Na⁺-K⁺-ATPase in animal models [4] (Fig. 1). This intriguing and timely study provides a novel strategy for treating neocortical epilepsy that is often induced by various acquired factors including trauma, infections, and neoplasms, and supplements the theories about astrocyte-neuron interactions.

Fig. 1.

Schematic of this study (modified from the original article [4]). Photostimulation of ChR2 on astrocytes allows the inward flow of Na⁺, which directly activates astrocytic Na⁺-K⁺-ATPase, leading to inward buffering of extracellular K⁺ and decreased neuronal excitability, resulting in the alleviation of neocortical seizures.

To selectively manipulate astrocytes, the authors transfected Cre-dependent channelrhodopsin-2 (ChR2) into the motor cortex of GFAP-Cre mice and demonstrated that photostimulation of astrocytes attenuated the seizure progression and eliminated the occurrence of generalized seizures in acute neocortical seizure models, and the anti-seizure effects were not restricted to specific frequencies of photostimulation. Interestingly, the anti-seizure effect of the photostimulation of astrocytes was associated with the suppression of the firing of pyramidal neurons in an activity-dependent and long-term manner. By in vivo electrophysiological recordings, they demonstrated that photostimulation of astrocytes had heterogeneous effects on the firing activity of pyramidal neurons with low-frequency basal activity (0 Hz–1 Hz). However, as the basal firing activity increased, the inhibitory effect of photostimulation became more prominent. According to the authors, photostimulation of astrocytes showed unified inhibition of all the recorded pyramidal neurons with relatively high-frequency basal activity (>5 Hz).

Notably, given such electrophysiological characteristics, the authors further designed elegant experiments to demonstrate the advantages of photostimulation of astrocytes in controlling neocortical seizures than directly modulating the cortical neurons. This therapy had a wider effective therapeutic time window, and applying photostimulation at both the early and late phases achieved good anti-seizure outcomes that were unreachable by directly inhibiting cortical pyramidal neurons. Also, this therapy was able to control seizures originating from the remote contralateral motor cortex, indicating a broad anti-seizure potential for neocortical epilepsy which is usually composed of extensive epileptogenic zones. Furthermore, to test whether this therapy was effective in chronic neocortical epilepsy, the authors established a focal cortical dysplasia (FCD) model which mimics clinically intractable neocortical epilepsy [5]. They found that photostimulation of astrocytes successfully lowered the seizure stages and extended the seizure latency in the FCD model.

Finally, the authors investigated the exact acting mechanisms of this therapy. Given that astrocytic Ca²⁺ signaling is critical for astrocytic transmitter releases and the modulation of neuronal activity [6], the authors performed pharmacological experiments to test whether astrocytic Ca²⁺ signaling was involved. However, neither thapsigargin (a non-competitive inhibitor of the sarco/endoplasmic reticulum Ca²⁺ ATPase) nor BAPTA-AM (a cell-permeant Ca²⁺ chelator) reversed the anti-seizure effect of photostimulation. Further chemogenetic experiments demonstrated that Ca²⁺ signaling was not involved. Then the authors turned to investigate the role of astrocytic Na⁺-K⁺-ATPase, which might be activated by Na⁺ entry due to the ChR2 activation [7]. Interestingly, either using ouabain (an inhibitor of Na⁺-K⁺-ATPase) or AAV-GFAP-shRNA(Atp1α2)-GFP (aimed at the genetic knockdown of Na⁺-K⁺-ATPase) successfully reversed the anti-seizure and neuronal inhibitory effect of photostimulation. This solid evidence demonstrated that the astrocytic Na⁺-K⁺-ATPase-mediated buffering of K⁺ contributes to its anti-seizure effects.

Overall, this study proposes the photostimulation of astrocytes as an effective and promising treatment for neocortical epilepsy, it challenges the notion that activated astrocytes are mainly pro-epileptic, and it supplements the theories of astrocyte-neuron interactions by highlighting the role of Na⁺-K⁺-ATPase-mediated buffering of K⁺. We further address some issues that may be of further translational importance: (1) extending the therapeutic potential to other types of epilepsy such as temporal lobe epilepsy, which has the highest incidence of pharmacoresistance [8, 9], may further broaden the scope of clinical applications; (2) since astrocytes may be morphologically activated and involved in epileptogenesis in glioma-related epilepsy [10], it is worth exploring whether this therapy has a similar effect under those conditions; and (3) given that directly performing optogenetic manipulations for patients is still difficult, directly modulating astrocytes with more feasible methods remains a challenge. However, Rome was not built in a day; inspired by the findings of this study, efforts can be directed towards further developing potential drugs or manipulation approaches aimed at astrocytic Na⁺-K⁺-ATPase activation for neocortical epilepsy treatment.

Conflict of interest

The authors declare that they have no competing interests.