Seizures rapidly impair phosphorylation-dependent regulatory mechanisms of KCC2.
epilepticus, the development of prolonged or repetitive epileptiform activity without
recovery in between, is a medical emergency. The vast majority of biomedical research
applied to SE treatment has focused on targeting the GABAA receptor to promote neuronal
inhibition. Little attention is given to the mechanism that establishes hyperpolarizing
GABAA receptor currents in the... read moreadult brain. The K+-Cl- cotransporter KCC2 has been well
established as the primary chloride extrusion mechanism in adult neurons that generates
the low intracellular Cl- concentration necessary for fast synaptic inhibition. The
major findings of this study are 1) phosphorylation of KCC2 at S940 is necessary for
surviving kainate-induced SE, 2) phosphorylation of KCC2 at T906 contributes to the
behavioral and electrographic seizures observed upon SE induction, and 3)
phosphorylation of KCC2 at T906 may be mediated by Wnk3 kinase. These findings improve
our understanding of the mechanisms underlying the development SE, which could in turn
lead to novel therapeutic strategies for the treatment of this debilitating and deadly
Thesis (Ph.D.)--Tufts University, 2013.
Submitted to the Dept. of Neuroscience.
Advisors: Stephen Moss, and Jamie Maguire.
Committee: Chris Dulla, Dan Co, and Kristopher Kahle.
Keyword: Neurosciences.read less