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

Autor: Fatima S. Elgammal, Akshata A. Korgaonkar, Vijayalakshmi Santhakumar, Bogumila Swietek, Ying Li, Stella Elkabes, Jianfeng Wang
Rok vydání: 2015
Předmět:
Male
Innate immune response
Time Factors
Wistar
Neurodegenerative
Hippocampal formation
Hippocampus
Tissue Culture Techniques
Traumatic brain injury
Receptors
AMPA
2.1 Biological and endogenous factors
Aetiology
Neurons
Chemistry
Mossy cell
Synaptic Potentials
Electrophysiology
medicine.anatomical_structure
Neurology
Neurological
Disease Progression
NMDA receptor
N-Methyl-D-Aspartate
Agonist
Physical Injury - Accidents and Adverse Effects
medicine.drug_class
Clinical Sciences
Glutamic Acid
AMPA receptor
Receptors
N-Methyl-D-Aspartate
Article
lcsh:RC321-571
Glutamatergic
medicine
Animals
Dentate gyrus
Rats
Wistar
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
Brain Concussion
Traumatic Head and Spine Injury
Excitability
Epilepsy
Neurology & Neurosurgery
Animal
Neurosciences
medicine.disease
Granule cell
Rats
Brain Disorders
Toll-Like Receptor 4
Disease Models
Animal
NMDA
Disease Models
Excitatory Amino Acid Antagonists
Neuroscience
Zdroj: Neurobiology of Disease, Vol 74, Iss, Pp 240-253 (2015)
ISSN: 0969-9961
DOI: 10.1016/j.nbd.2014.11.021
Popis: 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 hours, which peaked at 24 hours. 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.
Databáze: OpenAIRE
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