Neuronal Toll-like Receptor-4 regulation of Matrix Metalloproteinase-9 Activity Mediates Dentate Circuit Dysfunction after Traumatic Brain Injury

Neuroinflammatory pathways activated by traumatic brain injury (TBI) are critical mediators of long-term neurological dysfunction and represent promising therapeutic targets. Toll-like receptor 4 (TLR4), an innate immune receptor, was previously shown to contribute to seizure susceptibility and cognitive deficits in rats after lateral fluid percussion injury (FPI). However, the cellular and molecular mechanisms underlying TLR4-mediated circuit dysfunction early after brain injury is not fully understood. In this study, we define a cell- and circuit- specific neuroimmune-extracellular matrix signaling axis that mediates early post-TBI circuit dysfunction in the hippocampal Dentate Gyrus (DG). Using ex vivo electrophysiology in rat and mouse models one-week after brain injury, we demonstrate that neuronal TLR4 signaling regulates both excitatory and inhibitory synaptic inputs to dentate granule cells (DGC). Pharmacological inhibition of TLR4 in rats within 24 hours post-injury and cell-type-specific deletion of TLR4 in glutamatergic neurons in mice demonstrated that injury-driven excitatory circuit dysfunction is mediated by neuronal TLR4 and relies on downstream activation of Matrix Metalloproteinase-9 (MMP-9), an enzyme critical for extracellular matrix remodeling. In contrast, TLR4-dependent alterations in inhibitory inputs occurred independent of MMP-9, revealing a mechanistic divergence. Early inhibition of either TLR4 signaling or MMP-9 activity in rats within 24 hours post-injury reduced network hyperexcitability, improved long-term potentiation (LTP) in the dentate gyrus measured in vivo one-week after injury, and attenuated long-term deficits in spatial memory one-month post-injury. Furthermore, we demonstrate a context-dependent role for TLR4 signaling contributing to circuit homeostasis in the uninjured brain and driving circuit dysfunction in the injured brain. Together, these results identify a novel TLR4 -MMP-9 axis as a key driver of early post-TBI dentate gyrus circuit dysfunction and behavioral deficits.