Open AccessAquaporin-4 Reduces Post-Traumatic Seizure Susceptibility by Promoting Astrocytic Glial Scar Formation in Mice
Author(s) -
Daniel C. Lu,
Zsolt Zádor,
Jinghua Yao,
Farbod Fazlollahi,
Geoffrey T. Manley
Publication year - 2021
Publication title -
journal of neurotrauma
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.653
H-Index - 149
eISSN - 1557-9042
pISSN - 0897-7151
DOI - 10.1089/neu.2011.2114
Subject(s) - epileptogenesis , medicine , traumatic brain injury , astrocytosis , aquaporin 4 , minocycline , microglia , epilepsy , glial fibrillary acidic protein , anesthesia , pathology , inflammation , immunohistochemistry , biology , psychiatry , microbiology and biotechnology , antibiotics
Seizures are important neurological complications after traumatic brain injury (TBI) and are reported for up to 50% of patients with TBI. Despite several studies, no drug strategy has been able to alter the biological events leading to epileptogenesis. The glial water channel, aquaporin-4 (AQP4), was shown to facilitate cytotoxic cell swelling in ischemia and glial scar formation after stab wound injury. In this study, we examined post-traumatic seizure susceptibility of AQP4-deficient mice (AQP4 -/- ) after injection of pentylenetetrazole (PTZ) 1 month after controlled cortical impact (CCI) and compared them to wild-type sham injury controls. After PTZ injection, AQP4 -/- mice demonstrated dramatically shortened seizure latency (120 ± 40 vs. 300 ± 70 sec; p < 0.001) and increased seizure severity (grade 7.5 ± 0.4 vs. 5.8 ± 0.4; p < 0.001) compared to their wild-type counterparts. Morphometric analysis demonstrated a significant 2-fold reduction in astrocytosis, with a concomitant increase in microgliosis in injured AQP4-null mice compared to their injured wild-type counterparts (44 ± 2 vs. 24 ± 3 cells per high power field [cells/hpf], respectively; p < 0.0001). Minocycline, an inhibitor of microglia, reversed the post-TBI epilepsy phenotype of AQP4-null mice. After minocycline treatment, AQP4 -/- mice demonstrated similar latency of seizures evoked by PTZ (723 ± 35 vs. 696 ± 38 sec; p > 0.05) and severity of seizures evoked by PTZ (grade 4.0 ± 0.5 vs. 3.81 ± 0.30; p > 0.05) compared to wild-type counterparts. Immunohistochemical analysis demonstrated decreased immunostaining of microglia to levels comparable to wild-type (12 ± 2 vs. 11 ± 4 cells/hpf, respectively; p > 0.05). Taken together, these results suggest a protective role of AQP4 in post-traumatic seizure susceptibility by promoting astrogliosis, formation of a glial scar, and preventing microgliosis.