RGS7 Protein Suppression of Gao Protein‐Mediated α2A‐Adrenergic Receptor Inhibition of Mouse Hippocampal CA3 Epileptiform Activity

G‐protein coupled α 2 adrenergic receptor (AR) activation by epinephrine (EPI) inhibits epileptiform activity in the mouse hippocampal CA3 region. The mechanism underlying this action is unclear. This study investigated which subtypes of α 2 ARs, G‐proteins (Gα o or Gα i ), and RGS proteins were involved in this response using recordings of hippocampal CA3 epileptiform bursts in mouse brain slices. First, we determined that this effect was mediated by the α 2A AR subtype as the inhibitory action of EPI on epileptiform burst frequency was abolished in slices from α 2A AR, but not α 2C AR, knockout mice. Next, using transgenic mice with the G184S Gnai2 allele (knock‐ins) which interrupts G‐protein α unit binding to regulators of G‐protein signaling (RGS), we found that the α 2A AR antiepileptic effects of EPI were enhanced in hippocampal slices from mutant Gα o mice but not Gα i2 mice. Finally, hypomorph mice with very low RGS7 protein levels were found to have increased α 2A AR‐mediated hippocampal antiepileptic actions compared to their littermate controls. These results indicate that the EPI‐mediated inhibition of mouse hippocampal CA3 epileptiform burst activity is through an α 2A AR/Gα o ‐mediated pathway under strong inhibitory control by proteins of the RGS7 family. This suggests a possible role for selective α 2A AR agonists or RGS7 inhibitors as a novel antiepileptic drug therapy.