An update for epilepsy research and antiepileptic drug development: Toward precise circuit therapy

Wang, Yi; Zhong, Chen

doi:10.1016/j.pharmthera.2019.05.010

Cited by 110 publications

(68 citation statements)

References 256 publications

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“…The abnormal network that arises during seizure activities in TLE has not yet been thoroughly investigated, especially the limbic brain regions that are distant from the seizure focus 45 . Our study aimed to establish the specific role of SNr GABAergic neurons and PV subtype neurons in TLE models.…”

Section: Discussionmentioning

confidence: 99%

A disinhibitory nigra-parafascicular pathway amplifies seizure in temporal lobe epilepsy

Chen

Wang

et al. 2020

Nat Commun

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The precise circuit of the substantia nigra pars reticulata (SNr) involved in temporal lobe epilepsy (TLE) is still unclear. Here we found that optogenetic or chemogenetic activation of SNr parvalbumin + (PV) GABAergic neurons amplifies seizure activities in kindling-and kainic acid-induced TLE models, whereas selective inhibition of these neurons alleviates seizure activities. The severity of seizures is bidirectionally regulated by optogenetic manipulation of SNr PV fibers projecting to the parafascicular nucleus (PF). Electrophysiology combined with rabies virus-assisted circuit mapping shows that SNr PV neurons directly project to and functionally inhibit posterior PF GABAergic neurons. Activity of these neurons also regulates seizure activity. Collectively, our results reveal that a long-range SNr-PF disinhibitory circuit participates in regulating seizure in TLE and inactivation of this circuit can alleviate severity of epileptic seizures. These findings provide a better understanding of pathological changes from a circuit perspective and suggest a possibility to precisely control epilepsy.

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Section: Discussionmentioning

confidence: 99%

A disinhibitory nigra-parafascicular pathway amplifies seizure in temporal lobe epilepsy

Chen

Wang

et al. 2020

Nat Commun

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“…2 It is often medically refractory from a clinical therapeutic standpoint due to its frequent resistance to antiepileptic drugs and surgical resection. [3][4][5] In addition, although neuromodulation using vagus nerve stimulation, transcranial magnetic stimulation, or deep brain stimulation has become new options for epilepsy treatment, 6 the responder rate is still relatively low 7 and inconsistent results are often produced, 8 possibly due to the non-specific effect. Poor control of epileptic seizures together with unexpected injuries caused by seizures and other complications brings heavy burdens to the patients.…”

Section: Introductionmentioning

confidence: 99%

Pharmaco‐genetic inhibition of pyramidal neurons retards hippocampal kindling‐induced epileptogenesis

et al. 2020

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“…In recent years, the public has become increasingly concerned about epilepsy (Novotna and Rektor, 2017). The specific occurrence of epilepsy and the molecular mechanisms of its development are still not completely clear (Perucca and Perucca, 2019;Wang and Chen, 2019).…”

Section: Introductionmentioning

confidence: 99%

Olfactomedin-3 Enhances Seizure Activity by Interacting With AMPA Receptors in Epilepsy Models

Tang

Wang

Zhang

et al. 2020

Front. Cell Dev. Biol.

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Background: OLFM3 (olfactomedin-3) is a member of the olfactomedin domain family, which has been found to stimulate the formation and adhesion of tight cell connections and to regulate cytoskeleton formation and cell migration. Differences in the gene coding for OLFM3 have been found between patients with epilepsy and controls. However, the exact role of OLFM3 in epilepsy has not been thoroughly investigated. Methods: Biochemical methods were used to assess OLFM3 expression and localization in the cortex of patients with temporal lobe epilepsy and in the hippocampus and cortex of epileptic mice. Electrophysiological recordings were used to measure the role of OLFM3 in regulating hippocampal excitability in a model of magnesium-free-induced seizure in vitro. Behavioral experiments were performed in a pentylenetetrazol (PTZ)-induced seizure model, and electroencephalograms (EEGs) were recorded in the chronic phase of the kainic acid (KA)-induced epilepsy model in vivo. OLFM3 and its interaction with AMPAR (α-amino-3-hydroxy-5-methyl-4isoxazole-propionic acid receptor) subunits were analyzed by co-immunoprecipitation. Results: The expression of OLFM3 was increased in the cortex of patients with temporal lobe epilepsy and in the hippocampus and cortex of epileptic mice compared with controls. Interestingly, lentivirus-mediated overexpression of OLFM3 in the hippocampus increased the susceptibility of mice to PTZ-induced seizures, and OLFM3 knockdown had the opposite effect. OLFM3 affected AMPAR currents in a brain-slice model of epileptiform activity induced by Mg2+-free medium. We found that OLFM3 co-immunoprecipitation with GluA1 and GluA2. Furthermore, downregulation or overexpression of OLFM3 in the hippocampus affected the membrane expression of GluA1 and GluA2 in epileptic mice. Conclusion: These findings reveal that OLFM3 may enhance seizure activity by interacting with GluA1 and GluA2, potentially indicating a molecular mechanism for new therapeutic strategies.

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An update for epilepsy research and antiepileptic drug development: Toward precise circuit therapy

Cited by 110 publications

References 256 publications

A disinhibitory nigra-parafascicular pathway amplifies seizure in temporal lobe epilepsy

A disinhibitory nigra-parafascicular pathway amplifies seizure in temporal lobe epilepsy

Pharmaco‐genetic inhibition of pyramidal neurons retards hippocampal kindling‐induced epileptogenesis

Olfactomedin-3 Enhances Seizure Activity by Interacting With AMPA Receptors in Epilepsy Models

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