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 4h, which peaked at 24h. 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.
authors.affiliation: Department of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department 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.
authors.forename: Akshata A
authors.initials: AA
authors.lastname: Korgaonkar
authors.affiliation: Department of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Bogumila
authors.initials: B
authors.lastname: Swietek
authors.affiliation: Department of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology and Neurosciences, Rutgers New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Fatima S
authors.initials: FS
authors.lastname: Elgammal
authors.affiliation: Graduate 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, USA.
authors.forename: Stella
authors.initials: S
authors.lastname: Elkabes
authors.affiliation: Department 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. Electronic address: santhavi@njms.rutgers.edu.
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Santhakumar
mesh_terms: D000818:Animals; D001924:Brain Concussion / Q000503:physiopathology*; D018891:Dentate Gyrus / Q000187:drug effects / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055366:Synaptic Potentials / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D046509:Tissue Culture Techniques; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D018698:Glutamic Acid
keywords: AMPA; Dentate gyrus; Electrophysiology; Excitability; Hippocampus; Innate immune response; Mossy cell; NMDA; Traumatic brain injury