GABAergic Control of the HPA axis as a Treatment Target for Epilepsy.
Abstract: In response
to stress, the hypothalamic pituitary adrenal (HPA) axis is activated and the stress
hormone corticosterone is released from the adrenal gland in mice. Stress is a common
trigger for seizures, and epileptic patients have increased levels of stress hormones.
We hypothesize that HPA activation following a single seizure episode may result in
future seizure susceptibility ... read moredue to the pro-convulsant effects of corticosterone. Our
data demonstrate that a single seizure episode is sufficient to activate the HPA axis
and increase circulating levels of corticosterone. Consistent with the pro-convulsant
effects of corticosterone, attenuating the output of the HPA axis reduced seizure
susceptibility. Our data suggest that increased levels of corticosterone during and
following seizures could be mediating the creation of a pro-epileptic environment. Thus,
insight into the regulation of the HPA axis associated with seizure activity might have
significant implications for seizure control. Neurons controlling the HPA axis are
largely regulated by GABAergic inhibition. The chloride co-transporters KCC2 and NKCC1
maintain the chloride gradient which is essential for GABAA mediated hyperpolarization.
Here we demonstrate that KCC2 is down-regulated and functionally impaired, and NKCC1
up-regulated, in the paraventricular nucleus (PVN) of the hypothalamus, compromising
GABAergic inhibition and contributing to HPA hyperexcitability following seizures.
Further our data suggest that treatment with the NKCC1 inhibitor bumetanide decreases
seizure susceptibility in adult animals. These data suggest that impaired GABAergic
inhibition in neurons controlling the HPA axis create a pro-epileptic environment and
bumetanide may be a novel target for seizure
Thesis (M.S.)--Tufts University, 2012.
Submitted to the Dept. of Neuroscience.
Advisor: Kathleen Dunlap.
Committee: Chris Dulla, Stephen Moss, and Jamie Maguire.
Keyword: Neurosciences.read less