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- Title
Reactive Astrogliosis Causes the Development of Spontaneous Seizures.
- Authors
Robel, Stefanie; Buckingham, Susan C.; Boni, Jessica L.; Campbell, Susan L.; Danbolt, Niels C.; Riedemann, Therese; Sutor, Bernd; Sontheimer, Harald
- Abstract
Epilepsy is one of the most common chronic neurologic diseases, yet approximately one-third of affected patients do not respond to anticonvulsive drugs that target neurons or neuronal circuits. Reactive astrocytes are commonly found in putative epileptic foci and have been hypothesized to be disease contributors because they lose essential homeostatic capabilities. However, since brain pathology induces astrocytes to become reactive, it is difficult to distinguish whether astrogliosis is a cause ora consequence of epileptogenesis. We now present a mouse model of genetically induced, widespread chronic astrogliosis after conditional deletion of β1-integrin (Itgβ1). In these mice, astrogliosis occurs in the absence of other pathologies and without BBB breach or significant inflammation. Electroencephalography with simultaneous video recording revealed that these mice develop spontaneous seizures during the first six postnatal weeks of life and brain slices show neuronal hyperexcitability. This was not observed in mice with neuronal-targeted β1-integrin deletion, supporting the hypothesis that astrogliosis is sufficient to induce epileptic seizures. Whole-cell patch-clamp recordings from astrocytes further suggest that the heightened excitability was associated with impaired astrocytic glutamate uptake. Moreover, the relative expression of the cation-chloride cotransporters (CCC) NKCC1 (Slc12a2) and KCC2 (Slc12a5), which are responsible for establishing the neuronal Cl- gradient that governs GABAergic inhibition were altered and the NKCC1 inhibitor bumetanide eliminated seizures in a subgroup of mice. These data suggest that a shift in the relative expression of neuronal NKCC1 and KCC2, similar to that observed in immature neurons during development, may contribute to astrogliosis-associated seizures.
- Subjects
GLIOSIS; SPASMS; EPILEPSY; ASTROCYTES; ELECTROENCEPHALOGRAPHY; LABORATORY mice; DIAGNOSIS
- Publication
Journal of Neuroscience, 2015, Vol 35, Issue 8, p3330
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1574-14.2015