β3-Adrenergic receptor-dependent modulation of the medium afterhyperpolarization in rat hippocampal CA1 pyramidal neurons.

Action potential firing in hippocampal pyramidal neurons is regulated by generation of an afterhyperpolarization (AHP). Three phases of AHP are recognised, with the fast AHP regulating action potential firing at the onset of a burst, and the medium and slow AHPs supressing action potential firing over 100s of milliseconds and seconds respectively. Activation of β-adrenergic receptors suppresses the slow AHP by a protein kinase A-dependent pathway. However, little is known regarding modulation of the medium AHP. Application of the selective β-adrenergic receptor agonist isoproterenol suppressed both the medium and slow AHPs evoked in rat CA1 hippocampal pyramidal neurons recorded from slices maintained in organotypic culture. Suppression of the slow AHP was mimicked by intracellular application of cAMP, with the suppression of the medium AHP by isoproterenol still being evident in cAMP-dialysed cells. Suppression of both the medium and slow AHPs was antagonised by the β-adrenergic receptor antagonist propranolol. The effect of isoproterenol to suppress the medium AHP was mimicked by two β3-adrenergic receptor agonists: BRL37344 and SR58611A. The medium AHP was mediated by activation of SK and deactivation of H channels at the resting membrane potential. Suppression of the medium AHP by isoproterenol was reduced by pre-treating cells with the H-channel blocker ZD7288. These data suggest that activation of β3-adrenergic receptors inhibits H-channels, which suppresses the medium AHP in CA1 hippocampal neurons by utilising a pathway that is independent of a rise of intracellular cAMP. This finding highlights a potential new target in modulating H-channel activity, and thereby neuronal excitability.