Toll-like receptor 4 enhancement of non-NMDA synaptic currents increases dentate excitability after brain injury

Ying Li; Akshata A. Korgaonkar; Bogumila Swietek; Jianfeng Wang; Fatima S. Elgammal; Stella Elkabes; Vijayalakshmi Santhakumar

doi:10.1016/j.nbd.2014.11.021

Toll-like receptor 4 enhancement of non-NMDA synaptic currents increases dentate excitability after brain injury

Ying Li, Akshata A. Korgaonkar, Bogumila Swietek, Jianfeng Wang, Fatima S. Elgammal, Stella Elkabes, Vijayalakshmi Santhakumar

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

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.

Original language	American English
Pages (from-to)	240-253
Number of pages	14
Journal	Neurobiology of Disease
Volume	74
DOIs	https://doi.org/10.1016/j.nbd.2014.11.021
State	Published - Feb 1 2015

ASJC Scopus subject areas

Neurology

Keywords

AMPA
Dentate gyrus
Electrophysiology
Excitability
Hippocampus
Innate immune response
Mossy cell
NMDA
Traumatic brain injury

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10.1016/j.nbd.2014.11.021

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title = "Toll-like receptor 4 enhancement of non-NMDA synaptic currents increases dentate excitability after brain injury",

abstract = "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.",

keywords = "AMPA, Dentate gyrus, Electrophysiology, Excitability, Hippocampus, Innate immune response, Mossy cell, NMDA, Traumatic brain injury",

author = "Ying Li and Korgaonkar, {Akshata A.} and Bogumila Swietek and Jianfeng Wang and Elgammal, {Fatima S.} and Stella Elkabes and Vijayalakshmi Santhakumar",

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AU - Li, Ying

AU - Korgaonkar, Akshata A.

AU - Swietek, Bogumila

AU - Wang, Jianfeng

AU - Elgammal, Fatima S.

AU - Elkabes, Stella

AU - Santhakumar, Vijayalakshmi

PY - 2015/2/1

Y1 - 2015/2/1

N2 - 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.

AB - 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.

KW - AMPA

KW - Dentate gyrus

KW - Electrophysiology

KW - Excitability

KW - Hippocampus

KW - Innate immune response

KW - Mossy cell

KW - NMDA

KW - Traumatic brain injury

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DO - 10.1016/j.nbd.2014.11.021

M3 - Article

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SN - 0969-9961

VL - 74

SP - 240

EP - 253

JO - Neurobiology of Disease

JF - Neurobiology of Disease

ER -

Toll-like receptor 4 enhancement of non-NMDA synaptic currents increases dentate excitability after brain injury

Abstract

ASJC Scopus subject areas

Keywords

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