Upregulation of Matrix Metalloproteinase-9 by Toll-like Receptor 4 Contributes to Functional Deficits After Brain Injury
Abstract number :
1.012
Submission category :
1. Basic Mechanisms / 1A. Epileptogenesis of acquired epilepsies
Year :
2025
Submission ID :
940
Source :
www.aesnet.org
Presentation date :
12/6/2025 12:00:00 AM
Published date :
Authors :
Presenting Author: Deepak Subramanian, PhD – University of California - Riverside
Erick Contreras, BS – University of California - Riverside
Laura Dovek, PhD – University of California - Riverside
Iryna Ethell, PhD – University of California - Riverside
Viji Santhakumar, PhD – University of California, Riverside
Rationale: Traumatic brain injury (TBI) initiates a cascade of secondary events that exacerbate the initial damage contributing to long-term neurological dysfunction. Our previous work demonstrated that Toll-like Receptor 4 (TLR4) signaling promotes epileptogenesis and cognitive impairments in rats after lateral fluid percussion injury (FPI). However, the mechanisms linking TLR4 to neuronal excitability and plasticity remain unclear. Here, we identify a novel TLR4-dependent upregulation of Matrix Metalloproteinase-9 (MMP-9) activity as a potential mechanistic link between TLR4 signaling and circuit changes in the hippocampal dentate gyrus (DG) following brain injury.
Methods: Juvenile rats (P24–28) underwent moderate FPI (2.0±1atm) and were assessed for changes in synaptic currents, network excitability, long-term potentiation (LTP) using in-vitro and in-vivo electrophysiology, and spatial memory using Barnes maze.
Results: Whole-cell patch-clamp recordings revealed an increase in excitatory and a decrease in inhibitory synaptic current frequency in the dentate granule cells 1-week post-injury. This was attenuated by TLR4 inhibition (n=7–8 cells/group, p< 0.0001, KS test). In-situ zymography revealed a TLR4 mediated upregulation MMP-9 activity in the dentate gyrus 48 hours after FPI (n=5 animals/group, p< 0.05 by TW-ANOVA). RNAscope experiments revealed that TLR4 signaling transcriptionally upregulated MMP-9 via NF-kB indicating a potential mechanism for TLR4 regulation of synaptic changes after brain injury. Supporting this hypothesis, MMP-9 inhibition mitigated post-injury changes to excitatory synaptic currents (n=7–8 cells/group, p< 0.0001, KS test). However, post-injury changes in inhibitory currents were not reduced by MMP-9 inhibition suggesting a TLR4 dependent but MMP-9 independent mechanism underlying inhibitory plasticity after FPI.
Basic Mechanisms