Toll-like receptor 4 enhancement of non-NMDA synaptic currents increases dentate excitability after brain injury
Concussive brain injury results in neuronal degeneration, microglial activation and enhanced excitability in the hippocampal dentate gyrus, increasing the risk for epilepsy and memory dysfunction. Endogenous molecules released during injury can activate innate immune responses including toll-like re...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2015-02-01
|
Series: | Neurobiology of Disease |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996114003672 |
id |
doaj-cedf6e5ad0be4f969199bcedd1a0d2f3 |
---|---|
record_format |
Article |
spelling |
doaj-cedf6e5ad0be4f969199bcedd1a0d2f32021-03-22T12:42:16ZengElsevierNeurobiology of Disease1095-953X2015-02-0174240253Toll-like receptor 4 enhancement of non-NMDA synaptic currents increases dentate excitability after brain injuryYing Li0Akshata A. Korgaonkar1Bogumila Swietek2Jianfeng Wang3Fatima S. Elgammal4Stella Elkabes5Vijayalakshmi Santhakumar6Department of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ 07103, USADepartment of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ 07103, USA; Graduate School of Biomedical Sciences, Rutgers New Jersey Medical School, Newark, NJ 07103, USADepartment of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ 07103, USADepartment of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ 07103, USADepartment of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ 07103, USAGraduate School of Biomedical Sciences, Rutgers New Jersey Medical School, Newark, NJ 07103, USA; Department of Neurological Surgery, Rutgers New Jersey Medical School, Newark, NJ 07103, USADepartment of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ 07103, USA; Graduate School of Biomedical Sciences, Rutgers New Jersey Medical School, Newark, NJ 07103, USA; Department of Pharmacology and Physiology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA; Corresponding author at: Department of Neurology and Neurosciences, Rutgers New Jersey Medical School, MSB-H-512, 185 S. Orange Ave. Newark, NJ 07103, USA. Fax: +1 973 972 5059.Concussive brain injury results in neuronal degeneration, microglial activation and enhanced excitability in the hippocampal dentate gyrus, increasing the risk for epilepsy and memory dysfunction. Endogenous molecules released during injury can activate innate immune responses including toll-like receptor 4 (TLR4). Recent studies indicate that immune mediators can modulate neuronal excitability. Since non-specific agents that reduce TLR4 signaling can limit post-traumatic neuropathology, we examined whether TLR4 signaling contributes to early changes in dentate excitability after brain injury. Concussive brain injury caused a transient increase in hippocampal TLR4 expression within 4 h, which peaked at 24 h. Post-injury increase in TLR4 expression in the dentate gyrus was primarily neuronal and persisted for one week. Acute, in vitro treatment with TLR4 ligands caused bidirectional modulation of dentate excitability in control and brain-injured rats, with a reversal in the direction of modulation after brain injury. TLR4 antagonists decreased, and agonist increased, afferent-evoked dentate excitability one week after brain injury. NMDA receptor antagonist did not occlude the ability of LPS-RS, a TLR4 antagonist, to decrease post-traumatic dentate excitability. LPS-RS failed to modulate granule cell NMDA EPSCs but decreased perforant path-evoked non-NMDA EPSC peak amplitude and charge transfer in both granule cells and mossy cells. Our findings indicate an active role for TLR4 signaling in early post-traumatic dentate hyperexcitability. The novel TLR4 modulation of non-NMDA glutamatergic currents, identified herein, could represent a general mechanism by which immune activation influences neuronal excitability in neurological disorders that recruit sterile inflammatory responses.http://www.sciencedirect.com/science/article/pii/S0969996114003672Traumatic brain injuryDentate gyrusHippocampusElectrophysiologyInnate immune responseExcitability |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ying Li Akshata A. Korgaonkar Bogumila Swietek Jianfeng Wang Fatima S. Elgammal Stella Elkabes Vijayalakshmi Santhakumar |
spellingShingle |
Ying Li Akshata A. Korgaonkar Bogumila Swietek Jianfeng Wang Fatima S. Elgammal Stella Elkabes Vijayalakshmi Santhakumar Toll-like receptor 4 enhancement of non-NMDA synaptic currents increases dentate excitability after brain injury Neurobiology of Disease Traumatic brain injury Dentate gyrus Hippocampus Electrophysiology Innate immune response Excitability |
author_facet |
Ying Li Akshata A. Korgaonkar Bogumila Swietek Jianfeng Wang Fatima S. Elgammal Stella Elkabes Vijayalakshmi Santhakumar |
author_sort |
Ying Li |
title |
Toll-like receptor 4 enhancement of non-NMDA synaptic currents increases dentate excitability after brain injury |
title_short |
Toll-like receptor 4 enhancement of non-NMDA synaptic currents increases dentate excitability after brain injury |
title_full |
Toll-like receptor 4 enhancement of non-NMDA synaptic currents increases dentate excitability after brain injury |
title_fullStr |
Toll-like receptor 4 enhancement of non-NMDA synaptic currents increases dentate excitability after brain injury |
title_full_unstemmed |
Toll-like receptor 4 enhancement of non-NMDA synaptic currents increases dentate excitability after brain injury |
title_sort |
toll-like receptor 4 enhancement of non-nmda synaptic currents increases dentate excitability after brain injury |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2015-02-01 |
description |
Concussive brain injury results in neuronal degeneration, microglial activation and enhanced excitability in the hippocampal dentate gyrus, increasing the risk for epilepsy and memory dysfunction. Endogenous molecules released during injury can activate innate immune responses including toll-like receptor 4 (TLR4). Recent studies indicate that immune mediators can modulate neuronal excitability. Since non-specific agents that reduce TLR4 signaling can limit post-traumatic neuropathology, we examined whether TLR4 signaling contributes to early changes in dentate excitability after brain injury. Concussive brain injury caused a transient increase in hippocampal TLR4 expression within 4 h, which peaked at 24 h. Post-injury increase in TLR4 expression in the dentate gyrus was primarily neuronal and persisted for one week. Acute, in vitro treatment with TLR4 ligands caused bidirectional modulation of dentate excitability in control and brain-injured rats, with a reversal in the direction of modulation after brain injury. TLR4 antagonists decreased, and agonist increased, afferent-evoked dentate excitability one week after brain injury. NMDA receptor antagonist did not occlude the ability of LPS-RS, a TLR4 antagonist, to decrease post-traumatic dentate excitability. LPS-RS failed to modulate granule cell NMDA EPSCs but decreased perforant path-evoked non-NMDA EPSC peak amplitude and charge transfer in both granule cells and mossy cells. Our findings indicate an active role for TLR4 signaling in early post-traumatic dentate hyperexcitability. The novel TLR4 modulation of non-NMDA glutamatergic currents, identified herein, could represent a general mechanism by which immune activation influences neuronal excitability in neurological disorders that recruit sterile inflammatory responses. |
topic |
Traumatic brain injury Dentate gyrus Hippocampus Electrophysiology Innate immune response Excitability |
url |
http://www.sciencedirect.com/science/article/pii/S0969996114003672 |
work_keys_str_mv |
AT yingli tolllikereceptor4enhancementofnonnmdasynapticcurrentsincreasesdentateexcitabilityafterbraininjury AT akshataakorgaonkar tolllikereceptor4enhancementofnonnmdasynapticcurrentsincreasesdentateexcitabilityafterbraininjury AT bogumilaswietek tolllikereceptor4enhancementofnonnmdasynapticcurrentsincreasesdentateexcitabilityafterbraininjury AT jianfengwang tolllikereceptor4enhancementofnonnmdasynapticcurrentsincreasesdentateexcitabilityafterbraininjury AT fatimaselgammal tolllikereceptor4enhancementofnonnmdasynapticcurrentsincreasesdentateexcitabilityafterbraininjury AT stellaelkabes tolllikereceptor4enhancementofnonnmdasynapticcurrentsincreasesdentateexcitabilityafterbraininjury AT vijayalakshmisanthakumar tolllikereceptor4enhancementofnonnmdasynapticcurrentsincreasesdentateexcitabilityafterbraininjury |
_version_ |
1724208285294264320 |