Written by Fei Fan

Editor-in-charge - Wang Sizhen

Editor — Binwei Yang

Epilepsy is one of the most common disorders of the nervous system, affecting nearly 1 percent of the global population and nearly one-third of patients with symptoms that are difficult to control by antiepileptic drugs [1

On August 25, 2022, the Chen Zhong team from Zhejiang University/Zhejiang University of Traditional Chinese Medicine published a research paper

The hippocampus is the most common focal point of temporal lobe epilepsy, and the lower support, as the main output portal of hippocampal signaling, has received widespread attention

Fig.

(Source: Fei F, et al.

First, the researchers used the classic mouse hippocampal electric ignition TLE model[13] to find that glutamatergic neurons in the lower tray are highly activated in temporal lobe seizures, and the activated neurons are mainly concentrated in the deep layers

Then, in the neural circuit tracking experiment, the researchers found that the glutamatergic neurons of the lower support were widely projected

Fig.
2 The glutaminergic neural circuit of the lower tray-prethalamic nucleus bidirectionally regulates temporal lobe seizures

(Source: Fei F, et al.
, Nat Commun, 2022)

The researchers then modulated the glutamate projection loop of lower-ant, and found that optogenetic activation of this circuit can significantly promote the formation of epilepsy and sGS, which is even stronger than the regulation of overall lower-trophic glutamate neurons
.

Conversely, optogenetics inhibition of the projection loop of tropo-ANT significantly inhibits the epilepsy formation process and sGS (Figure 2
).

The above results indicate that the glutaminergic neural circuit of lower trope-ANT plays a bidirectional regulatory role in the sGS of
TLE.

At the same time, the researchers also paid attention to the regulatory effects of the other three glutamatergic neural circuits, lower troph-EC, lower troph-NAc and lower troph-MMB on epilepsy, and found that when the troph-EC circuit was inhibited, the formation process of epilepsy was accelerated
compared with the control group.

In addition, when the mice were fully ignited, the inferior togotaminergic neuron endings that inhibited EC projection slightly prolonged the ADD and GSD
at the time of seizures.

In contrast, the lower trophglutaergic neuronal endings that inhibit NAc and MMB projection have no significant effect on seizures
(Figure 3).

These results suggest that neural circuits projecting downstream to different brain regions downstream are heterogeneous in the regulation of TLE episodes
.

Fig.
3 The lower support-endocorphal cortex, the lower support-papillary body, and the lower support-accumbens glutamatergic neural circuit play different roles in temporal lobe epilepsy

(Source: Fei F, et al.
, Nat Commun, 2022)

In the KA-induced model of chronic epilepsy [14], the researchers combined chemogenetics with long-term inhibition of the lower to-ANT and -EC loops, and similarly found that local administration of CNO in ANT reduced the number and duration of seizures; When CNO is injected topically into EC, both the number of seizures and the total duration of seizures in mice increase (Figure 4
).

These results suggest that glutamatergic neurons in the lower tray differentially regulate seizures through different downstream circuits, where the lower tray-ANT and lower tray-EC circuits have opposite effects on seizures
.

Fig.
4 The lower-thalamus prenucleus and lower-trophodococcal glutamatergic circuitry play the opposite role in KA-induced chronic epilepsy

(Source: Fei F, et al.
, Nat Commun, 2022)

So what causes the differential action of lower tonutreergic neurons? It is highly likely that glutaminergic neurons that are understarted to dominate different downstream brain regions are anatomically grouped and transmit different epilepsy signals
.

To test this conjecture, the researchers first injected reverse marker viruses carrying different fluorescences into different downstream brain regions to track
them.

The results showed that ant-projected neurons were almost completely located in the deep part of the lower support (that is, the lower support area that was mainly activated after epilepsy), while the EC-projected neurons were mainly distributed in the superficial layer of the lower support, and the two were completely separated
.

Next, the researchers used the Axon-GCaMP6s virus to further detect changes in calcium signaling at the level of the lower tray-ANT and lower tray-EC loops during the onset of
TLE.

The results showed that in the early stages of the seizure, the calcium signal of the ANT endings increased, while the EC decreased accordingly; When the sGS phase is reached, the calcium signaling intensity of the ANT endings increases delayed with the development of the seizures and returns to the basic state with the termination of epilepsy; At the end of ecclesiastically, after a seizure, calcium signaling drops (transient transient elevation) to below the basal status level (Figure 5
).

These results suggest that the functional response of these two subpots of lower tolutaminergic neurons to TLE is independent and opposite, where ANT-projected neurons are positively responding to seizures, while EC-projected neurons are inhibited instead of activity
in epilepsy.

Fig.
5 Subpopules of lower tray neurons projected by the prethalamic nucleus and the endophthalmic cortex respond differently in temporal lobe epilepsy

(Source: Fei F, et al.
, Nat Commun, 2022)

The researchers subsequently recorded in vivo multichannels of ANT-projected deep lower-trophic neurons and EC-projected shallow lower-trophic neurons, and found that deep-seated glutamate neurons had stronger cluster firing capacity (Figure 6a-d
).

Further ex vivo electrophysiology shows that ant-projected lower trophlutaminergic neurons, especially cluster-fired neurons, have large inward currents of hyperpolarization activation, suggesting that their hyperpolarized activated cyclic nucleotide-gated cation (HCN) channels may be more functional and exhibit stronger clustered discharge capabilities
.

Incubation of HCN channel antagonists can attenuate this cluster firing capacity to some extent (Figure 6e-m), suggesting that the function of the HCN channel may have promoted the cluster firing capacity of ANT-projected lower trophlutaminergic neurons
.

Fig.
6 Subpopulations of hypotropic neurons projected by the prethalamic nucleus have cluster firing capabilities promoted by HCN channels

(Source: Fei F, et al.
, Nat Commun, 2022)

The researchers finally administered the antagonist directly to the lower tray and specifically knocked down the HCN channel on the ANT-projected neurons of the lower tray by shRNA, and found that there was a significant inhibitory effect on the seizures
.

Further, since cluster discharge plays an important role in enhancing the plasticity of neural circuits, finally, the researchers used experiments to test circuit plasticity in vivo single pulses and found that the support-ANT circuits under the lower tropHN antagonist or optogenetic inhibition during epilepsy formation significantly weakened the intensity of the electrical signals transmitted from the lower hordes in ANT (Figure 7).
Suggesting the enhanced effect of clustered firing of neurons involved in the HCN channel in the generalization of temporal lobe epilepsy, suggesting that the HCN channel in the lower trope-ANT neural circuit is an important intervention target for
temporal lobe epilepsy.

Fig.
7 Synaptic plasticity involved in the HCN channel in the lower tray-prethalamic nucleus loop accelerates the formation and generalization of temporal lobe epilepsy

(Source: Fei F, et al.
, Nat Commun, 2022)

Conclusions and discussions, inspiration and prospects Of this study, this study is the first to find that neurons in different subregions of lower support have differentiated (or even opposite) effects
on the regulation of "excitatory-inhibition" balance in temporal lobe epilepsy through different projection downstreams.

Among them, the cluster discharge mediated by superpolar activation of cation-activated cation gated channels (HCN) in the neural circuits projecting to the prethalamus nucleus of the lower bracket closely enhances the formation and generalization of temporal lobe epilepsy, suggesting the importance of precise intervention in temporal lobe epilepsy and an important supplement
to the pathogenesis of temporal lobe epilepsy in the lower portal.

However, the number and function of the clustered distribution nerves of the lower tray before and after epilepsy are still unknown
.

How to use a more accurate method to specifically regulate the lower trophlutamic energy neurons projected by ANT is also a challenge
for future research.

In addition, the lower-trophic glutamate and GABA-enabled neurons are also subjected to a large number of upstream nerve inputs, and this study reveals whether there are differences in the upstream excitatory/inhibitory inputs received in the heterogeneous lower-tropic nerve circuits, and how they are involved in the regulation of temporal lobe epilepsy, which needs to be further explored
.

Original link: first author of the study is Fei Fan, a doctoral student at the School of Pharmacy of Zhejiang University (now a postdoctoral fellow at Zhejiang University of Traditional Chinese Medicine), Wang Xia, a master's student, and Xu Layerlin, a researcher at Zhejiang University of Traditional Chinese Medicine, and Professor Chen Zhong, Researcher Wang Yi, and Researcher Xu Layerlin are the corresponding authors
of this paper.

The research has been funded by the National Natural Science Foundation of China, the National Natural Science Foundation of China, and the Zhejiang Provincial Natural Science Foundation
.

First author: Fei Fan (tenth from the left in the third row) Wang Xia (thirteenth from the left in the third row) Researcher Xu Layerlin (sixth from the left in the second row); Corresponding authors: Professor Chen Zhong (fourth from the left in the second row), Researcher Wang Yi (fifth from the left in the second row) and Researcher Xu Layerlin

(Photo source: Professor Chen Zhong's laboratory)

Selected articles from previous issues

[1] Mol Psychiatry-Wang Yingfei research group revealed the role of KDM6B protein in neuronal synaptic plasticity and learning and memory

[2] Cereb Cortex—The Team of Shanbao Tong/Xiangfei Hong reveals important influencing factors of EEG alpha rhythm in the visuospatial attention task

[3] Cereb Cortex— Excavation and analysis of imaging subtypes for the heterogeneity of schizophrenia

[4] Front Cell Neurosci Review:Gamma Neural Oscillation and Central Nervous System Diseases: Mechanisms and Therapeutic Advances

[5] The NAR-He Cheng/Su Zhida team found that topoisomerase IIA can regulate adult neurogenesis in the subependymal region

[6] The Sci Adv-Liao Wenbo team has made important progress in the adaptive evolution of amphibian brain volume

[7] J Neuroinflammation—From Changchun/Jian Zhang's team found that targeting proteoglycan receptors after hemorrhagic stroke protects white matter integrity and promotes the recovery of neurological function

[8] Front Aging Neurosci—Zeng Yanbing's team established a predictive model and revealed the effects of behavioral changes on cognitive impairment in the elderly

[9] Sci Adv-Zhao Cunyou/Chen Rongqing team revealed the mechanism of microRNA inducing social and memory abnormalities in mice: miR-501-3p expression defects enhance glutamate delivery

[10] Sci Adv-Zhang Yi's research group found important neurons that regulate drug addiction behavior

Recommended for high-quality scientific research training courses

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End of this article