Clenbuterol reduces GABAergic transmission in prefrontal cortex layer 5/6 pyramidal neurons of juvenile rat via reducing action potentials firing frequency of GABAergic interneurons

Abstract

Beta-adrenoceptors (β₂ -ARs) have beneficial effects on prefrontal cortex (PFC) working memory, however, the cellular and molecular mechanisms are unclear yet. In this study, we probed the effect of β₂ -AR-selective agonist clenbuterol (Clen) on synaptic transmission in layer 5/6 pyramidal neurons of PFC. Bath application of Clen reduced spontaneous IPSC (sIPSC) frequency without effects on sEPSCs. Clen did not alter the frequency and amplitude of miniature IPSCs (mIPSCs), but exerted heterogeneous effects on evoked IPSCs (eIPSCs) recorded from PFC layer 5/6 pyramidal neurons. Clen decreased the firing rate of action potentials of fast-spiking GABAergic interneurons. Clen-induced hyperpolarization of fast-spiking GABAergic interneurons required potentiation of an inward rectifier K⁺ channels. Clen-induced hyperpolarization of fast-spiking interneurons was dependent on Gs protein rather than cAMP and protein kinase A. Our findings demonstrate that Clen (10 μM) enhances inward rectifier K⁺ channels via Gs protein to cause membrane hyperpolarization of fast-spiking GABAergic interneurons resulting in reduction of action potentials firing rate to reduce GABAergic transmission.

Keywords: GABAergic transmission; clenbuterol; inward rectifier K+ channel; prefrontal cortex.