Beta-estradiol increases dentate gyrus inhibition in female rats via augmentation of hilar neuropeptide Y.
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 beta-estradiol in ovariectomized rats protects hilar interneurons against seizure-induced injury, including the NPY-containing damage-sensitive subpopulation. Here, we demonstrate that beta-estradiol enhances NPY expression within the hilar interneurons. In vitro paired-pulse stimulation of the mixed perforant path revealed beta-estradiol-induced augmentation of granule cell network inhibition, which at interstimulus intervals between 200 and 300 ms (corresponding to approximately 3-5 Hz) was NPY sensitive and involved Y1 receptors, whereas it was insensitive to GABA(B) or metabotropic glutamate receptor antagonists. Additionally, beta-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 beta-estradiol alone. Together, we show that beta-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, beta-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.
Velísková
Jana
J
Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy, Albert Einstein College of Medicine and the Einstein/Montefiore Comprehensive Epilepsy Management Center, Bronx, New York 10461, USA. jvelisko@aecom.yu.edu
Velísek
Libor
L
D000818:Animals; D018891:Dentate Gyrus / Q000187:drug effects* / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D005260:Female; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009478:Neuropeptide Y / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy / Q000503:physiopathology
D009478:Neuropeptide Y; D004958:Estradiol