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The Nat Commun-Chen Zhong/Wang team revealed a new mechanism by which astrocytes are involved in seizures

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Written by - Zhao Junli edited - Wang Sizhen, Fang Yiyi edited - Wang Sizhen
epilepsy It is one of the most common neurological diseases, affecting nearly 1% of the global population, and nearly one-third of patients have symptoms that are difficult to control by anti-seizure drugs and become drug-resistant epilepsy [1].

Among them, cortical epilepsy is a more common type of drug-resistant epilepsy, so it is particularly urgent to study its pathogenesis and therapeutic targets
.
The study of the classical seizure mechanism mainly focuses on the "excition-inhibition" imbalance of neurons, and the existing anti-seizure drugs are almost all based on neurons as drug targets.

In recent years, more and more studies have found that "astrocytes-neurons" interactions play an important role in epilepsy [2].

However, researchers have been unable to clarify the role of astrocytes in the process of epilepsy and progression, mainly due to the lack of specific means to regulate astrocytes and accurately distinguish the effects of astrocytes on peripheral neurons [3].

Recently, the team of Professor Chen Zhong and Wang Yi of Zhejiang University/Zhejiang University of Chinese Medicine published an online report in the journal Nature Communications “Activated astrocytes attenuate neocortical seizures in rodent models through driving Na⁺-K⁺- ATPase"
.
The team has been engaged in the analysis of the pathogenesis of epilepsy and the discovery of therapeutic drug targets, focusing on the balance mechanism of the neural circuit "excitation-inhibition" with hippocampal fossular as the core, the regulatory treatment strategy and the research
of new drug targets in the pathogenesis of epilepsy.
This study further revealed the mechanism of astrocytes involved in seizures on the basis of previous research, and found that the study specifically activated Na+-K+ of cortical astrocytes through optogenetic means -ATPase, thereby achieving the effect of treating neocortical epilepsy, provides new ideas and potential targets for the treatment of refractory epilepsy
.
(Further reading: The latest progress of Chen Zhong & Wang Yi's team, see the "Logical Neuroscience" report (click to read) for details.
) ：Nat Commun | Chen Zhong's team revealed the circuit and molecular mechanism of Xiatuo's involvement in the onset of temporal lobe epilepsy.
Research—Chen Zhong's team revealed the circuit mechanism of CaMKIIα+ neurons in the lateral hypothalamus to regulate predation behavior; Current Biology—Chen Zhong's team has achieved new results in histamine-regulated feeding mechanism: H2 receptor-dependent medial septum histamineergic circuit; SCI Adv-Chen Zhong's team proposed a new idea of epilepsy drug treatment: electroresponsive polydopamine nanodrug delivery system).

First, the researchers specifically expressed the light-sensitive channel protein ChR2 into astrocytes in the mouse cortex, and used the cortical epilepsy KA (sea human acid) model to find that blue light stimulation was given at different stages of epilepsy, including the whole process, early and late stages (early and late stages with epilepsy grade 2 as the cut-off point).
can achieve anticortical epilepsy
.
Further, the researchers gave blue light stimulation on the opposite side of the epileptic focus point and found that it could still exert anti-epileptic effects (Figure 1), suggesting that light stimulation of astrocytes can exert long-term anti-epileptic effects and inhibit epileptic transmission
.

Figure 1 Optogenetically stimulates ChR2-expressing astrocytes to reduce cortical seizures (Source: Zhao et al.
, Nat Commun, 2022)
So, does optogenetic stimulation of astrocytes affect neuronal activity? The researchers used the method of recording the activity of single cells in the body to record the activity
of surrounding pyramidal excitatory neurons while stimulating astrocytes with blue light.
Interestingly, blue light stimulates astrocytes to inhibit the activity of neurons dependently, that is, neurons with low firing frequency have heterogeneous responses to light, while neurons with high firing frequency are significantly inhibited
.
Moreover, after the blue light stops stimulating astrocytes, the inhibitory effect on neurons will continue for some time
.
During the KA-induced seizure state, neurons in the brain become highly synchronized to fire, at which point the blue light stimulates ChR2-expressing astrocytes to significantly and prolong-term inhibit neuronal activity (Figure 2)
。

Figure 2: Optogenetic stimulation of astrocyte activity-dependent inhibition of cortical pyramidal cell activity

(Source: Zhao et al.
, Nat Commun, 2022).

Since optogenetic stimulation of astrocytes works by inhibiting excitatory neurons, why not directly inhibit excitatory neurons in the cortex? The researchers then used optogenetic methods to directly inhibit cortical excitatory neurons (expressing ArchT to excitatory pyramidal neurons), consistent with the pattern of stimulating astrocytes, and the whole optogenetic selective inhibition of pyramidal neurons can play a similar antiepileptic effect
.
However, inhibition of pyramidal neurons only in the early or late stages of epilepsy does not have an antiepileptic effect
.
At the same time, inhibition of pyramidal neurons on the opposite side of the epileptic focus point also does not produce an antiepileptic effect (Figure 3).

The researchers also found that unlike light-stimulating astrocytes, photoinhibiting neurons impairs the mice's luck function
.
These results show that optogenetics directly inhibits the antiepileptic effect of excitatory neurons in a narrow time window, cannot play a long-term anti-seizure and propagation effect, and there are also side effects
that affect motor function.

Figure 3 Optogenetic inhibition of cortical excitatory neurons alleviates cortical epilepsy, but the time window is narrow (Source: Zhao et al.
, Nat Commun, 2022
So, how does optogenetic stimulation of astrocytes affect neuronal activity? Since ChR2 can permeate cations, cations such as^Ca2+, Na⁺ flow into the cell along a concentration gradient[4].

。 Among them, the increased C2+ signaling of astrocytes plays a crucial role in glial transmitter release and neuronal activity regulation[5].

Therefore, the researchers first used pharmacological means to block the Ca2+ signal in astrocytes, and found that blocking the^Ca2+ signal of astrocytes could not reverse the anti-epileptic effect
of photostimulation.
Next, the researchers used chemogenetics to specifically activate the Ca2+ signal of astrocytes, and found that the ^Ca2+ enhancement of astrocytes not only could not simulate the effect of anti-epilepsy, but also promoted the occurrence of epilepsy in the early stage (Figure 4).

The above results suggest that the Ca2+ signaling of astrocytes is itself involved in early seizures, but does not mediate the anti-epileptic effect
of light stimulation of astrocytes.

Figure 4: The antiepileptic effect of optogenetic stimulation of astrocytes is independent of ^Ca2+ signaling (Source: Zhao et al.
, Nat Commun, 2022)
So, what mediates the antiepileptic effect of stimulating astrocytes? The researchers hypothesized that since ChR2 also permeates Na+ into cells, Na⁺ entering the cell activates the Na of astrocytes ⁺-K⁺-ATPase, which will be an excess of K+ in the extracellular environment What about buffering into astrocytes? To test this idea, the researchers used pharmacological and shRNA genetic methods to block Na+-K⁺ in astrocytes - A2 subunit of ATPase, the results showed that the antiepileptic effect of light stimulation of astrocytes was reversed
.
Moreover, blocking Na+-K⁺-ATPase in astrocytes can simultaneously reverse the inhibitory effect
on neurons in single-cell recordings.
Further studies have found that when optogenetics stimulates astrocytes, the concentration of K+ in extracellular cerebrospinal fluid decreases, and a wide network of antiepileptic anti-epileptic is generated through the gap junction of astrocytes (Figure 5).
）
。
Figure 5 Na+-K⁺-ATPase of astrocytes Mediated the antiepileptic effect of optogenetic stimulation of astrocytes (Source: Zhao et al.
, Nat Commun, 2022).

The researchers finally further verified that optogenetic stimulation of astrocytes can reverse the seizure susceptibility of the FCD model in a chronic focal cortical dysplasia (FCD) model (Figure 6).

。 Since FC is an important trigger for refractory cortical epilepsy, this result suggests Na+-K⁺- in astrocytes ATPase is an important target for the treatment of refractory epilepsy
。
Figure 6: Photostimulation of astrocytes reverses rat FCD by Na+-K+-ATPase Model susceptibility to epilepsy (Source: Zhao et al.
, Nat Commun, 2022)
Figure 7 Optogenetics activates astrocytes through passing Summary diagram of Na+-K⁺-ATPase anti-epileptic (Source: Zhao et al.
, Nat Commun, 2022)
article conclusion and discussion, inspiration and prospects

In summary, this study found for the first time that optogenetic activation of astrocytes exhibits the following advantages compared with direct inhibition of neurons:( 1) the therapeutic window of anti-epileptic effect is wide, and optogenetic activation of astrocytes in the early or late stage of epilepsy can produce therapeutic effects; (2) The anti-epileptic effect has a wide range of space, and activation of astrocytes on the distal side of the epileptic focus can still effectively reduce seizures; (3) The anti-epileptic effect has no obvious effect
on normal physiological functions.
Mechanistically, this study further found that optogenetic activation of astrocytes can activity-dependent inhibit high-frequency firing pyramidal neurons in seizures
。 This effect is not related to the classical A2+-mediated glial transmitter in astrocytes, but rather to Na+-K⁺-ATP on astrocytes ASE function is enhanced, which in turn mediates a large amount of extracellular potassium buffer during seizures and reduces neuroexcitability
.
This effect can further exert antiepileptic effects through a broad network of slit junctions between astrocytes (Figure 7).

These results suggest that optogenetic means specifically activate cortical astrocytes to enhance Na+-K⁺-ATPase function Thus, it can achieve the role of treating neocortical epilepsy, suggesting the Na+-K⁺-ATPase of astrocytes May be a potential intervention target
for epilepsy treatment.

Of course, there are still some problems
that need to be further solved in this study.
For example, it remains to be clear whether the current astral glial photoregulatory strategy can be applied to
other types of epilepsy, such as temporal lobe epilepsy with a high drug resistance rate.
At the same time, it is unclear
whether replacing ChR2 with other photoresponsive cation channels has a similar effect.
Optogenetic regulation itself is difficult to apply clinically, and further development of selective agonists targeting astrocyte Na+-K+-ATPase (or its subunits) may be a promising direction
.

Original link: _mstmutation="1" _istranslated="1"> The first authors of the study are Dr.
Zhao Junli and Master student Sun Jinyi, Professor Chen Zhong and Professor Wang Yi are the corresponding authors
of this paper.
The research has been supported
by the Key R&D Program of the Ministry of Science and Technology of the People's Republic of China, the Excellent Youth Project of the National Natural Science Foundation of China, and the Major Project of the Natural Science Foundation of Zhejiang Province.

Prof.
Zhong Chen/Prof.
Yi Wang team

(Photo courtesy of Prof.
Chen Zhong/Wang Yi's research group).

Welcome to scan the code to join Logical Neuroscience Literature learning 2 group remarks format: Name--Research field-Degree/Title/Title/ Position Selected articles from previous issues

[1] Review Article Recommendation Issue 1 - Selected Reviews of the Latest Frontiers in the Field of Neuroscience in Cell Journal (October 11-11, 2022)

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, et al.
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Nat Neurosci, 2015.
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Sontheimer,Glia as drivers of abnormal neuronal activity.
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