TY - JOUR
T1 - Estradiol facilitates the release of neuropeptide y to suppress hippocampus-dependent seizures
AU - Ledoux, Veronica A.
AU - Smejkalova, Tereza
AU - May, Renee M.
AU - Cooke, Bradley M.
AU - Woolley, Catherine S.
PY - 2009/2/4
Y1 - 2009/2/4
N2 - About one-third of women with epilepsy have a catamenial seizure pattern, in which seizures fluctuate with the menstrual cycle. Catamenial seizures occur more frequently when the ratio of circulating estradiol to progesterone is high, suggesting that estradiol is proconvulsant. We used adult female rats to test how estradiol-induced suppression of GABAergic inhibition in the hippocampus affects behavioral seizures induced by kainic acid. As expected, estradiol decreased the latency to initiate seizures, indicating increased seizure susceptibility. At the same time, however, estradiol also shortened the duration of late-stage seizures, indicating decreased seizure severity. Additional analyses showed that the decrease in seizure severity was attributable to greater release of the anticonvulsant neuropeptide, neuropeptide Y (NPY). First, blocking hippocampal NPY during seizures eliminated the estradiol-induced decrease in seizure duration. Second, light and electron microscopic studies indicated that estradiol increases the potentially releasable pool of NPY in inhibitory presynaptic boutons and facilitates the release of NPY from inhibitory boutons during seizures. Finally, the presence of estrogen receptor-α on large dense-core vesicles (LDCVs) in the hippocampus suggests that estradiol could facilitate neuropeptide release by acting directly on LDCVs themselves. Understanding how estradiol regulates NPY-containing LDCVs could point to molecular targets for novel anticonvulsant therapies.
AB - About one-third of women with epilepsy have a catamenial seizure pattern, in which seizures fluctuate with the menstrual cycle. Catamenial seizures occur more frequently when the ratio of circulating estradiol to progesterone is high, suggesting that estradiol is proconvulsant. We used adult female rats to test how estradiol-induced suppression of GABAergic inhibition in the hippocampus affects behavioral seizures induced by kainic acid. As expected, estradiol decreased the latency to initiate seizures, indicating increased seizure susceptibility. At the same time, however, estradiol also shortened the duration of late-stage seizures, indicating decreased seizure severity. Additional analyses showed that the decrease in seizure severity was attributable to greater release of the anticonvulsant neuropeptide, neuropeptide Y (NPY). First, blocking hippocampal NPY during seizures eliminated the estradiol-induced decrease in seizure duration. Second, light and electron microscopic studies indicated that estradiol increases the potentially releasable pool of NPY in inhibitory presynaptic boutons and facilitates the release of NPY from inhibitory boutons during seizures. Finally, the presence of estrogen receptor-α on large dense-core vesicles (LDCVs) in the hippocampus suggests that estradiol could facilitate neuropeptide release by acting directly on LDCVs themselves. Understanding how estradiol regulates NPY-containing LDCVs could point to molecular targets for novel anticonvulsant therapies.
KW - CA1
KW - Catamenial epilepsy
KW - Electron microscopy
KW - GABA
KW - Kainic acid
KW - Large dense-core vesicle
UR - http://www.scopus.com/inward/record.url?scp=59649091955&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=59649091955&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.4688-08.2009
DO - 10.1523/JNEUROSCI.4688-08.2009
M3 - Article
C2 - 19193892
AN - SCOPUS:59649091955
VL - 29
SP - 1457
EP - 1468
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 5
ER -