No abstract

Objective Traumatic brain injury is a major risk factor for acquired epilepsies, and understanding the mechanisms underlying the early pathophysiology could yield viable therapeutic targets. Growing evidence indicates a role for inflammatory signaling in modifying neuronal excitability and promoting epileptogenesis. Here we examined the effect of innate immune receptor Toll‐like receptor 4 (TLR4) on excitability of the hippocampal dentate gyrus and epileptogenesis after brain injury. Methods Slice and in vivo electrophysiology and Western blots were conducted in rats subject to fluid percussion brain injury or sham injury. Results The studies identify that TLR4 signaling in neurons augments dentate granule cell calcium‐permeable α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor (CP‐AMPAR) currents after brain injury. Blocking TLR4 signaling in vivo shortly after brain injury reduced dentate network excitability and seizure susceptibility. When blocking of TLR4 signaling after injury was delayed, however, this treatment failed to reduce postinjury seizure susceptibility. Furthermore, TLR4 signal blocking was less efficacious in limiting seizure susceptibility when AMPAR currents, downstream targets of TLR4 signaling, were transiently enhanced. Paradoxically, blocking TLR4 signaling augmented both network excitability and seizure susceptibility in uninjured controls. Despite the differential effect on seizure susceptibility, TLR4 antagonism suppressed cellular inflammatory responses after injury without impacting sham controls. Interpretation These findings demonstrate that independently of glia, the immune receptor TLR4 directly regulates post‐traumatic neuronal excitability. Moreover, the TLR4‐dependent early increase in dentate excitability is causally associated with epileptogenesis. Identification and selective targeting of the mechanisms underlying the aberrant TLR4‐mediated increase in CP‐AMPAR signaling after injury may prevent epileptogenesis after brain trauma. ANN NEUROL 2020;87:497–515

OBJECTIVE In acute traumatic brain injury, decompressive craniectomy is a common treatment that involves the removal of bone from the cranium to relieve intracranial pressure. The present study investigated whether neurological function following a severe spinal cord injury improves after utilizing either a durotomy to decompress the intradural space and/or a duraplasty to maintain proper flow of cerebrospinal fluid. METHODS Sixty-four adult female rats (n = 64) were randomly assigned to receive either a 3- or 5-level decompressive laminectomy (Groups A and B), laminectomy + durotomy (Groups C and D), or laminectomy + duraplasty with graft (Group E and F) at 24 hours following a severe thoracic contusion injury (200 kilodynes). Duraplasty involved the use of DuraSeal, a hydrogel dural sealant. Uninjured and injured control groups were included (Groups G, H). Hindlimb locomotor function was assessed by open field locomotor testing (BBB) and CatWalk gait analysis at 35 days postinjury. Bladder function was analyzed and bladder wall thickness was assessed histologically. At 35 days postinjury, mechanical and thermal allodynia were assessed by the Von Frey hair filament and hotplate paw withdrawal tests, respectively. Thereafter, the spinal cords were dissected, examined for gross anomalies at the injury site, and harvested for histological analyses to assess lesion volumes and white matter sparing. ANOVA was used for statistical analyses. RESULTS There was no significant improvement in motor function recovery in any treatment groups compared with injured controls. CatWalk gait analysis indicated a significant decrease in interlimb coordination in Groups B, C, and D (p < 0.05) and swing speed in Groups A, B, and D. Increased mechanical pain sensitivity was observed in Groups A, C, and F (p < 0.05). Rats in Group C also developed thermal pain hypersensitivity. Examination of spinal cords demonstrated increased lesion volumes in Groups C and F and increased white matter sparing in Group E (p < 0.05). The return of bladder automaticity was similar in all groups. Examination of the injury site during tissue harvest revealed that, in some instances, expansion of the hydrogel dural sealant caused compression of the spinal cord. CONCLUSIONS Surgical decompression provided no benefit in terms of neurological improvement in the setting of a severe thoracic spinal cord contusion injury in rats at 24 hours postinjury. Decompressive laminectomy and durotomy did not improve motor function recovery, and rats in both of these treatment modalities developed neuropathic pain. Performing a durotomy also led to increased lesion volumes. Placement of DuraSeal was shown to cause compression in some rats in the duraplasty treatment groups. Decompressive duraplasty of 3 levels does not affect functional outcomes after injury but did increase white matter sparing. Decompressive duraplasty of 5 levels led to neuropathic pain development and increased lesion volumes. Further comparison of dural repair techniques is necessary.