The role of deficits in KCC2-mediated ion transport in the development and severity of temporal lobe epilepsy
Abstract: Temporal lobe
epilepsy is the most common form of human epilepsy, believed to arise in part from
compromised GABAergic inhibition. GABAA receptors permit an inward chloride flux to
mediate membrane hyperpolarization and restrict neuronal firing. In most adult brain
neurons, the activity of the membrane expressed type 2 K+-Cl- cotransporter (KCC2)
maintains the low intracellular chlo... read moreride necessary for inward chloride flux through
GABAA receptors. Deficits in KCC2 are observed in brain tissue surgically removed from
refractory temporal lobe epilepsy patients and in animal models of epileptogenesis. How
these deficits affect the development and severity of temporal lobe epilepsy is unknown.
To test this, I first performed local field potential recordings in ex vivo brain slices
of the mouse temporal lobe to understand the role of KCC2 transport on network dynamics.
Using multiple in vitro models of epileptiform activity, I show that deficits in KCC2
transport increase the severity of seizure events through prolonging the clonic phase of
after-discharges. These results indicated that KCC2 mediated ion transport plays a
critical role in the mechanisms of seizure termination. Next, I sought to understand the
effects of KCC2 deficits in the pathophysiology of temporal lobe epilepsy. To test this,
I locally ablated KCC2 in subsets of CAMKII positive neurons in the adult mouse
hippocampus. The removal of KCC2 compromised GABAergic inhibitory signaling, confirming
the role of KCC2 in setting and maintaining the reversal potential of GABAAR mediated
anion flux (EGABA). Reducing KCC2 in the hippocampus in vivo resulted in spontaneous,
recurring generalized seizures. Furthermore, these mice developed hippocampal sclerosis,
characterized by reactive astrogliosis and neuronal loss. My results suggest KCC2 plays
a key role in hippocampal network function and the development and severity of temporal
Thesis (Ph.D.)--Tufts University, 2018.
Submitted to the Dept. of Neuroscience.
Advisor: Stephen Moss.
Committee: Jamie Maguire, Chris Dulla, Michele Jacobs, and Shilpa Kadam.
Keywords: Neurosciences, Biology, and Medicine.read less