Alpha‐1 adrenergic receptor regulation of seizures and neurodegeneration

Abstract

Neurogenesis has potential as a treatment for epilepsy and neurodegeneration. The endogenous neurotransmitter norepinephrine (NE) may be involved in promoting neurogenesis through the activation of α1 adrenergic receptors (ARs). This project aims to obtain additional evidence for a possible role of α1ARs in neurogenesis and seizures using transgenic mice overexpressing α1AARs or α1BARs or having no functional (knockout) α1AARs or α1BARs. When treated with the epileptogenic agent flurothyl and compared to controls, mice overexpressing α1AARs had more hippocampal interneurons and showed an increase in latency periods preceding seizures while α1BAR overexpressing mice had significantly fewer interneurons and exhibited an enhanced susceptibility to seizures. Electrophysiological recordings during application of an α1AR agonist produced a concentration‐dependent increase in action potential frequency in hippocampal interneurons in normal and α1BAR knockout mice, but not in α1AAR‐knockout mice. These findings are potentially very significant because they link α1AAR‐induced proliferation of interneurons to the antiepileptic actions of NE. Insight into these mechanisms may lead to new treatment strategies for epilepsy and other neurodegenerative diseases. Supported by ND EPSCoR through NSF EPS‐0447679, NSF CAREER 0347259, NIH 5P20RR017699 from the NCRR, and the American Physiological Society.