α1A‐Adrenergic receptor activation modulates pyramidal neuron excitability in CA1 hippocampus

Norepinephrine has gained interest as a potential anti‐epileptic therapy, given in vitro application of the catecholamine decreases episodes of neuron hyperexcitability. This is particularly noted in rat hippocampal preparations, however it is not well understood which adrenergic receptor (AR) mediates the effect. We have previously characterized a subset of hippocampal CA1 interneurons that functionally express α1A‐ARs. These interneurons contain mRNA transcripts for GAD65 and somatostatin, and predominate in stratum oriens. In this study we examined the functional consequences of α1A‐AR activation in CA1. Phenylephrine (PE), a selective α1‐AR agonist, produced a concentration‐dependent increase in action potential frequency in ~75% of CA1 interneurons, while decreasing action potential frequency in CA1 pyramidal cells. Both effects were abolished by pre‐treatment of slices with the selective α1A‐AR antagonist 5‐methylurapidil. Whole cell recordings of CA1 pyramidal cells revealed an increase in GABAergic spontaneous IPSCs following PE application, but no change in miniature IPSC frequency, suggesting PE acts pre‐synaptically. The ability of PE to decrease pyramidal cell activity was significantly inhibited by pre‐treatment with the GABA A receptor antagonist picrotoxin, though complete inhibition was not observed. However, picrotoxin in conjunction with cyclosomatostatin, a somatostatin receptor antagonist, fully abolished PE’s ability to modulate pyramidal cell activity. Together these results suggest that α1A‐AR activation depolarizes a subset of CA1 interneurons, prompting them to release GABA and somatostatin onto neighboring pyramidal cells. This data illustrates one mechanism by which norepinephrine may decrease neuron hyperexcitability in hippocampus, specifically in CA1.