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Cell Reports - "Wet matches that stop epilepsy from igniting", Chen Zhong/Wang Yi's team analyzes the significance of epilepsy interseizure treatment

 Last Update: 2022-12-30
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Written by - Lai Nancy edited - Wang Sizhen, Fang Yiyi edited - Mr.
Wang Sizhen
Jin Yong's novel once described: "Within a hundred steps around the poison, there will be an antidote", This is probably an expression of the concept
of "all things living together".
Our brain is made up of hundreds of millions of neurons in a dynamic excitatory-inhibitory balance, and the overexcitability of local neuronal "dry matches" can directly "ignite" seizures
。 Recently, researchers from Zhejiang University and Zhejiang University of Traditional Chinese Medicine found that around the locally excited neurons "dry matches", there is a group of endogenous protective neurons "wet matches", which play a key role
in delaying the development of epilepsy in a weak number.

On December 13, 2022, Chen Zhong/Wang Yi from Zhejiang University and Zhejiang University of Traditional Chinese Medicine The research team published a report entitled "Interictal period-activated" in the internationally renowned journal Cell Reports Neuronal ensemble in piriform cortex retards further seizure development"
.
The team has long been engaged in the analysis of the pathogenesis of epilepsy and the discovery of therapeutic drug targets, focusing on the "excited-inhibition" balance mechanism and regulatory therapeutic strategies of the neural circuit with hippocampal subfersus as the core in epilepsy and the research of new drug targets （Neuron, 2017; Ann Neurol, 2019, 2021; Biol Psychiat, 2020; Nat Nanotech, 2020; Nat Commun, 2020, 2022a,b; iScience, 2022, Science Adv, 2022）
。 In this study, the researchers used early gene-driven cell labeling technology, combined with optogenetics, pharmacogenetics and other regulatory methods, to reveal for the first time the role of two groups of neurons with different functions related to epileptic states in the piriform cortex of the brain, which is related to the proposed "interictal phase" Activated clusters of neurons may be an important time window and therapeutic target
for future epilepsy treatment.
Interictal phase" is associated with a group of neurons ("wet matches") that play an important role in delaying the early development of epilepsy, and the "interictal phase" is proposed Activated clusters of neurons may be an important time window and therapeutic target
for future epilepsy treatment.
(Further reading: The latest progress of Chen Zhong & Wang Yi's team, see the "Logical Neuroscience" report (click to read): Nat.
) Commun-Chen Zhong/Wang Yi's team revealed a new mechanism of astrocytes involved in seizures; 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)

epilepsy is one of the earliest confirmed diseases in the world.
Written accounts dating back to 4000 BC [1].

As a chronic brain disease, epilepsy affects approximately 50 million people worldwide and about 9 million people in China [1].

。 When people with epilepsy develop a brief involuntary convulsion (i.
e.
, partial or generalized seizures) in one part of the body or the entire body, sometimes accompanied by loss of consciousness and urinary incontinence, epilepsy has been feared, misunderstood, discriminated against and regarded as a social stigma for centuries, which seriously affects the quality of life
of patients and their families.
Although a variety of antiepileptic drugs targeting ion channels and GABA_A receptors are currently used to control seizures clinically, none of the existing antiepileptic drugs can cure or prevent epilepsy.
And about one-third of patients with epilepsy develop refractory epilepsy due to tolerance to multiple antiepileptic drugs [2].

Clinical symptoms of epilepsy (ranging from very brief loss of consciousness or muscle reflexes to severe and persistent convulsions, etc.
) are caused by sudden abnormal discharges from a group of brain cells within the brain, and different parts of the brain can be the site of abnormal discharge
.
Seizures are unpredictable, recurrent, and transient
.
Clinically, we often refer to the period between one seizure and the next as the interictal period [3], when in fact the interictal period occupies most of the time period
of people with epilepsy.
However, it is unclear
how and how the interictal phase and the episodic phase transition and influence each other.

In this study, the researchers first used early-stage gene-driven cell labeling (E-SARE) to label focal seizures (FS-Ens) in APir brain regions and clusters of neurons activated by the interictal phase (IP-Ens
).
Followed inMouse hippocampal electric ignition model (kindling model), the focal seizures (FOCAL) of these two groups of neurons were studied using in vivo calcium signal recording seizure, FS), the results showed a downward trend in calcium activity in FS (Figure 1E-1H), FS-Ens has a significant increase in calcium activity in FS (Figure 1I-1L) , indicating that IP-Ens and FS-Ens in APir are functionally distinct clusters of neurons, and IP-Ens is not involved FS
。
Figure 1 Labeling process of the E-SARE system and different calcium responses of two groups of neurons (Source: Lai, et al.
, Cell Rep, 2022).

Since the different participation of these two groups of neurons in seizure events suggests that the two groups of neurons are heterogeneous in some aspects, the authors analyzed the composition of their neuronal types, as well as the distribution of their numbers and spatial locations, and the results showed IP-Ens and FS-Ens Mainly excitatory glutamatergic neurons (with Figures 2C-2F); The total number of neurons labeled by FS-Ens is greater than that of IP-Ens; IP-Ens is mainly distributed in the shallow layer of APir (L2), while FS-Ens is mainly distributed in the deep layer of APir ( L3 and L4) (with Figure 2G).

Figure 2 Type, number and spatial distribution of IP-Ens and FS-Ens neurons

(Source: Lai, et al.
, Cell Rep, 2022).

Next, the authors further explored its specific effect on seizures, and found that direct activation of FS-Ens with light can induce seizures, while photoactivation of IP-Ens can not induce seizures, indicating that the epileptogenic ability of these two groups of neurons is different
.
Interestingly, activating a small group of FS-Ens is more epileptogenic than activating a large group of CaMKIIa-positive neurons (Figure 2), illustrate FS-Ens may be the causative neuron that actually causes epilepsy, and there may be other subsets of neurons (presumably IP-Ens)
in APir.

Figure 2: The role of photoactivation of different activity-dependent clusters of neurons (Source: Lai, et al.
, Cell Rep, 2022).

In order to further confirm the conjecture that IP-Ens may have antiepileptic effects, the authors based on the previous "in vitro induced interphase discharge prevented the occurrence of seizure events" Research reports [4,5], explored a set of intervention methods to improve IP-Ens' activity in vivo, and found that APir was activated with light in advance IP-Ens significantly delayed the progression of seizure formation (Figure 3).

Figure 3 IP-Ens has anti-epileptic effect in the Kindling model: photoactivation of IP-Ens significantly delays the formation and progression of epilepsy (Source: Lai, et al.
, Cell Rep, 2022)
Then the authors reverse-inhibited IP-Ens and found that it can promote the formation and progression of epilepsy (Figure 4), indicating that IP-Ens can regulate the formation process of epilepsy in both directions, confirming the sufficient necessity of its anti-epileptic effect
。
Figure 4: Photoinhibition of IP-Ens accelerates the progression of epilepsy formation (Source: Lai, et al.
, Cell Rep, 2022
The previous work is to explore the role it plays in the development of epilepsy, and the researchers continue to explore the role of IP-Ens in generalized seizure , GS).

Also in the kindling model, bidirectional regulation IP-Ens has no effect on GS; Early activation of IP-Ens also does not exert its role in inhibiting large seizures (Figure 5).

Although this is a "negative" result, it suggests a key message: IP-Ens has a time window of intervention effect when the disease progresses to GS IP-Ens may not be sufficient to produce a therapeutic effect
.

Figure 5 Regulation of IP-Ens had no effect on large seizures (Source: Lai, et al.
, Cell Rep, 2022
Next, the researchers explored the involvement of IP-Ens in GS, using calcium-signaled fiber optic recordings combined with c-fos Characterization of immunohistochemistry, IP-Ens was found to be involved in GS.

While the results of previous studies (Figure 1) showed that IP-Ens is not involved in FS, then from FS What happened to IP-Ens during the progress of GS? By reverse tracking virus tracing method, the upstream input tracking of IP-Ens after FS and GS was carried out, and the results showed that APir IP-Ens has different loop connections in the FS and GS states, and accepts more inputs when IP-Ens participates in the GS loop (Figure 6), hinting at IP-Ens there is a recombination
of neural circuits in the later stages of epilepsy.

Figure 6 IP-Ens is involved in the loop of large seizures through loop recombination (Source: Lai, et al.
, Cell Rep, 2022).

Finally, the authors analyzed Pir and CA3 during the two episodes of FS and GS It was found that early activation of IP-Ens can reduce the synchronization of the two brain regions during FS, but cannot affect the synchronization of the brain regions during GS (Figure 7), which partly explains why IP-Ens loses its anti-epileptic effect
during GS.

Figure 7: Activating IP-Ens reduces synchronicity between brain regions during FS (Source: Lai, et al.
, Cell Rep, 2022)
to make the therapeutic significance of targeting "interictal activated neuronal clusters" more convincing, The authors further validated the function of these two groups of neurons in a model of alginic acid (KA)-induced acute seizures (Figure 4).

It was found that the cell cluster "Seizure-Ens" that activated the seizure response, rather than the interictal response cell cluster "IP-Ens", could induce seizures (pictured 4D), which is consistent with the results observed in the ignition model (Figure 2).

At the same time, pharmacogenetic activation of IP-Ens reduces the severity of seizures, manifested by prolonging the latency of status epilepticus (Figure 4E).

These results suggest that IP-Ens can be applied to a variety of epilepsy animal models
as anti-epileptic target cells.

Figure 4 IP-Ens has antiepileptic effect in acute KA models: pharmacogenetic activation of IP-Ens prolongs the incubation period of status epilepticus (Source: Lai, et al.
, Cell Rep, 2022)
Figure 8: Summary of work Figure: Interictal activated neuronal frenulum in the piriform cortex of the brain delays the further development of seizures, therefore" Interictal" activated neuronal clusters may be important time windows and therapeutic targets
for future epilepsy treatments.
(Source: Lai, et al.
, Cell Rep, 2022) Article conclusion and discussion, inspiration and prospectsIn summary, In this study, the FS-Ens of APir mediated the onset and spread of epilepsy by using an activity-dependent viral marker tool combined with genetically encoded effectors to specifically label, visualize, and manipulate two groups of neurons with different functions associated with epilepsy status in APir.
This group of neurons may be part of an
epileptogenic network.
However, the IP-Ens of APir may be an intrinsic group of "self-repairing" neural clusters, a protective mechanism that the brain initiates after an early onset.
Activating them can delay the early progression
of epilepsy by desynchronization of the local epilepsy network.
It's as if the hundreds of millions of neurons in the brain are matchsticks, in the "optogenetic kindling model" model used in this study Kindling translates to "ignite", and blue light is that fire FS-Ens is like a "dry match" that can be easily "lit.
" ” Excitement triggers abnormal synchronization seizure discharge, and IP-Ens is like a "wet match" that will not be " Ignition" causes seizures, and also has "fire extinguishing effect"
.
In conclusion, this study reveals APirThe role of different activity response subsets in seizures suggests that interictal activated neural clusters may be potential targets for seizure prevention
.

Future directions include testing the antiepileptic effects of "interphase neural clusters" in other, more clinically representative animal models of epilepsy, as well as in other brain regions, and accurately characterizing the events that activate neuronal clusters at different times during the interictal period, thereby laying the foundation
for better clinical translational therapy.

_mstmutation="1" _msthash="162190" _msttexthash="7589139389">The first authors of the study are Nanxi Lai, a doctoral student at the School of Pharmacy of Zhejiang University, and Heming Cheng, a postdoctoral
fellow at Zhejiang University of Chinese Medicine.
Professor Chen Zhong and Professor Wang Yi are the corresponding authors
of this paper.

Chen Zhong/Wang Yi research team group photo (photo courtesy of: Chen Zhong/Wang Yi research team)

Welcome to scan the code to join logical neuroscience Literature Study 2 Group Remarks Format: Name--Research Field-Degree/Title/Title/PositionPast Article Selection【 1] Aging Cell| Du Yifeng's team revealed a new mechanism of long-term aerobic exercise against Alzheimer's disease memory decline [2] Nat Hum Behav—Wu Tangchun/Li Liming's team revealed how residents cook for health [3] CRPS—self-powered speech recognition system developed by Guo Wenxi/Wu Ronghui's research group of Xiamen University for the hearing impaired [4] J Neurosc—the first time! Spatial-temporal development patterns of perinatal thalamic morphology, microstructure and connectivity[5] Cell Rep—Li Fei/Li Weiguang/Zhang Xiaoyong/Mei Bing team proposed classification criteria
for autism social disorder based on synaptic cell biological characteristics[6] Expert comments iScience—Li Yan's team revealed the molecular mechanism of familial epilepsy [7] Cell Death Discov—Kang Jiuhong's team found that NRG1 is expected to be a new target for the treatment of schizophrenia caused by intrauterine growth restriction [8] Nature—Zhang Shicheng et al.
analyzed the design principle of DREADD, a chemical genetic tool based on muscarinic acetylcholine receptors [9] eLife—Chen Shuyi's team first revealed the m6A epitranscriptional regulation mechanism of state transition between neural progenitor cells and glial cells [10] Nature—Shi Songhai's research group revealed a new mechanism that regulates the spatial fine structure arrangement and loop assembly of neurons in the neocortex of the brain, NeuroAI Reading Club[1] NeuroAI Reading Club Launched—Exploring the Frontier Intersection
of Neuroscience and Artificial Intelligence Recommended High-quality Research Training Courses [1] Symposium on Patch Clamp and Optogenetics and Calcium Imaging Technology (January 7-8, 2023 Tencent Meeting)【2】The 10th NIR Training Camp (Online: 2022.
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Reference (Swipe Up and Down to Read).
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Epilepsy [J].
Nature Reviews.
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[3] Karoly P J, Freestone D R, Boston R, et al.
Interictal spikes and epileptic seizures: their relationship and underlying rhythmicity [J].
Brain, 2016, 139(Pt 4): 1066-78.
[4] Nakagawa M, Durand D.
Suppression of spontaneous epileptiform activity with applied currents [J].
Brain Res, 1991, 567(2): 241-7.
[5] Warren R J, Durand D M.
Effects of applied currents on spontaneous epileptiform activity induced by low calcium in the rat hippocampus [J].
Brain Res, 1998, 806(2): 186-95.

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