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Electroconvulsive Seizures in Rats and Fractionation of Their Hippocampi to Examine Seizure-induced Changes in Postsynaptic Density Proteins
Published on: August 15, 2017
Microglial Transient Receptor Potential Melastatin 2 Deficiency Accelerates Seizure Development via Increasing
Yingwei Xu1,2, Luyu Ye1,3, Zhisheng Li1
1Institute of Pharmacology & Toxicology NHC and CAMS Key Laboratory of Medical Neurobiology College of Pharmaceutical Sciences School of Medicine Zhejiang University Hangzhou China.
Abstract:
Epilepsy is one of the most common neurological disorders, characterized by the enhancement of neural excitability from a neurocentric perspective. Emerging evidence indicates that microglia play a pivotal role in the pathogenesis of epilepsy through complex and various mechanisms that is still not fully understood. In this study, we demonstrate that the deficiency of transient receptor potential melastatin 2 (TRPM2) channel, a calcium-permeable nonselective cation channel, significantly accelerates seizure development in multiple mouse seizure models, including MES- and pentylenetetrazole(PTZ)-induced seizure model, intrahippocampal KA model, hippocampal kindling model, without affecting seizure susceptibility in initial acute seizure. Notably, it is the deficiency of TRPM2 specifically in microglia, rather than in CaMKIIα+ excitatory neurons or PV+ interneurons, that primarily responsible for seizure development. Moreover, microglial TRPM2 deficiency increases the excitability of hippocampal pyramidal neurons by enhancing the AMPAR-mediated excitatory synaptic transmission independent of changes in the expression of inflammatory cytokines. These findings reveal a previously unrecognized, inflammation-independent mechanism by which microglial instead of neuronal TRPM2 channel contributes to seizure development, highlighting microglial TRPM2 as a novel potential therapeutic target for epilepsy by specifically targeting microglial TRPM2 channel.
Insights
Microglial TRPM2 channels accelerate epilepsy development by increasing neural excitability. Targeting these channels in microglia offers a novel therapeutic strategy for epilepsy treatment.
Area of Science:
- Neuroscience
- Immunology
- Channelopathies
Background:
- Epilepsy is a common neurological disorder characterized by heightened neural excitability.
- Microglia, the immune cells of the brain, are increasingly recognized for their role in epilepsy pathogenesis.
- The specific mechanisms underlying microglial involvement in epilepsy remain incompletely understood.
Purpose of the Study:
- To investigate the role of the transient receptor potential melastatin 2 (TRPM2) channel in epilepsy.
- To determine whether TRPM2 deficiency in specific cell types, particularly microglia, influences seizure development.
- To elucidate the mechanism by which microglial TRPM2 impacts neural excitability and epilepsy.
Main Methods:
- Utilized multiple mouse models of epilepsy, including MES, PTZ-induced seizures, intrahippocampal KA injection, and hippocampal kindling.
- Generated mice with TRPM2 channel deficiency specifically in microglia, excitatory neurons (CaMKIIα+), and interneurons (PV+).
- Assessed seizure susceptibility and severity, and measured hippocampal pyramidal neuron excitability and AMPA receptor-mediated synaptic transmission.
Main Results:
- TRPM2 channel deficiency significantly accelerated seizure development across various epilepsy models.
- This pro-epileptic effect was specifically attributed to the absence of TRPM2 in microglia, not in neurons.
- Microglial TRPM2 deficiency enhanced hippocampal pyramidal neuron excitability via increased AMPA receptor activity, independent of inflammatory cytokine changes.
Conclusions:
- Microglial TRPM2 channels play a critical, previously unrecognized role in promoting seizure development in epilepsy.
- The mechanism is independent of neuroinflammation, involving direct modulation of neuronal excitability.
- Targeting microglial TRPM2 channels presents a novel therapeutic avenue for epilepsy management.
