The role of deficits in KCC2-mediated ion transport in the development and severity of temporal lobe epilepsy
Kelley, Matt.
2018
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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 chlor... read moreide 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 lobe epilepsy.
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 - ID:
- vq280100t
- Component ID:
- tufts:28608
- To Cite:
- DCA Citation Guide EndNote
