Somatostatin sharpens the neuronal action potential by increasing K⁺ and decreasing Ca²⁺ conductances

Somatostatin (SST) is a neuropeptide whose biological function has initially been described in the hypothalamus. However, SST-expressing neurons are also found in the neocortex or hippocampus, and the majority of these neurons are GABAergic interneurons (INs), the so called SST-INs. Numerous studies on non-cortical cells suggest that SST acts via different K⁺ channels to dampen cell excitability, however questions remain as to the exact mechanisms whereby SST mediates these effects on cortical pyramidal cells (PCs). The present study analyzed the capacity of SST to inhibit action potential (AP) firing in layer II/III PCs of the anterior cingulate cortex (aCC). It is reported here that SST decreases PC excitability mainly via G protein-coupled inwardly rectifying potassium (GIRK) and Kv₇ channels. Furthermore, activation of GIRK and Kv₇ channels together with inhibition of voltage-gated Ca²⁺ channels (VGCCs) is responsible for SST-dependent inhibition of AP firing and increase in the afterhyperpolarization (AHP) amplitude following an AP. By analyzing single AP kinetics before and after SST exposure, this study further identifies Ca²⁺-activated K⁺ (K_Ca) channels as target molecules of SST receptor activation. In summary, the present study promotes our current understanding of the ionic mechanisms that lead to a SST-dependent loss in excitability.NEW & NOTEWORTHY G protein-coupled inwardly rectifying potassium (GIRK) and Kv₇ channels contribute to somatostatin- (SST-) dependent hyperpolarization of the resting membrane potential in cortical pyramidal cells. Inhibition of action potential firing by SST is mediated via activation of GIRK and Kv₇ channels and via inhibition of voltage-gated Ca²⁺ channels. Sharpening of the action potential by SST is mediated via modulation of concerted GIRK, Kv₇, Ca²⁺-activated K⁺ and voltage-gated Ca²⁺ channel activity.