title: Aquaporin-4 Reduces Post-Traumatic Seizure Susceptibility by Promoting Astrocytic Glial Scar Formation in Mice.
abstract: 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.
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Lu
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Zador
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Farbod
authors.initials: F
authors.lastname: Fazlollahi
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Manley
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000172:deficiency*; D001253:Astrocytes / Q000378:metabolism*; D000070642:Brain Injuries, Traumatic / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D002921:Cicatrix / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism; D012640:Seizures / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4