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The Journal of Neuroscience, May 30, 2007, 27(22):6054-6063; doi:10.1523/JNEUROSCI.0366-07.2007
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Neurobiology of Disease
ß-Estradiol Increases Dentate Gyrus Inhibition in Female Rats via Augmentation of Hilar Neuropeptide Y
Jana Velí andková
Libor Velí Saul R. Korey Department of Neurology and Dominick P. Purpura Department of Neuroscience, Laboratory of Developmental Epilepsy, Albert Einstein College of Medicine and the Einstein/Montefiore Comprehensive Epilepsy Management Center, Bronx, New York 10461
Correspondence should be addressed to Dr. Jana Velí
The dentate gyrus filters incoming activity into the hippocampus proper. It plays a role in learning and memory and in pathological states such as epilepsy. Some of hilar interneurons of the dentate gyrus express neuropeptide Y (NPY), which modulates granule cell activity. A subpopulation of the NPY-expressing inhibitory interneurons is sensitive to seizure-induced damage. Pretreatment with ß-estradiol in ovariectomized rats protects hilar interneurons against seizure-induced injury, including the NPY-containing damage-sensitive subpopulation. Here, we demonstrate that ß-estradiol enhances NPY expression within the hilar interneurons. In vitro paired-pulse stimulation of the mixed perforant path revealed ß-estradiol-induced augmentation of granule cell network inhibition, which at interstimulus intervals between 200 and 300 ms (corresponding to
3–5 Hz) was NPY sensitive and involved Y1 receptors, whereas it was insensitive to GABAB or metabotropic glutamate receptor antagonists. Additionally, ß-estradiol pretreatment attenuated propagation of low-frequency (3.3 or 5 Hz) burst activity through the dentate gyrus. Scavenging endogenous NPY by intracerebroventricular administration of anti-NPY antibody accelerated kainic acid-induced seizure onset and increased seizure-induced neuronal damage in the hilus compared with rats treated with ß-estradiol alone. Together, we show that ß-estradiol upregulates hilar NPY and that this leads to enhancement in dentate gyrus inhibition of incoming frequencies between 3 and 5 Hz. Such frequencies are similar to the discharge frequencies recorded during seizure initiation in some patients with epilepsy. Thus, ß-estradiol-induced NPY-sensitive filtering of 3–5 Hz frequencies may be an important regulator of incoming seizure activity, but it could also serve a physiological purpose in modulating information flow into the hippocampus proper.
Key words: epilepsy; dentate gyrus; neuronal excitability; neuroprotection; estradiol; neuropeptide Y
Received Sept. 29, 2006; revised May 2, 2007; accepted May 5, 2007.
Correspondence should be addressed to Dr. Jana Velí
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