Somatostatin depresses the excitability of subicular bursting cells: Roles of inward rectifier K channels, KCNQ channels and Epac.

The hippocampus is a crucial component for cognitive and emotional processing. The subiculum provides much of the output for this structure but the modulation and function of this region is surprisingly under-studied. The neuromodulator somatostatin (SST) interacts with five subtypes of SST receptors (sst to sst ) and each of these SST receptor subtypes is coupled to Gi proteins resulting in inhibition of adenylyl cyclase (AC) and decreased level of intracellular cAMP. SST modulates many physiological functions including cognition, emotion, autonomic responses and locomotion. Whereas SST has been shown to depress neuronal excitability in the subiculum, the underlying cellular and molecular mechanisms have not yet been determined. Here, we show that SST hyperpolarized two classes of subicular neurons with a calculated EC of 0.1 μM. Application of SST (1 μM) induced outward holding currents by primarily activating K channels including the G-protein-activated inwardly-rectifying potassium channels (GIRK) and KCNQ (M) channels, although inhibition of cation channels in some cells may also be implicated. SST-elicited hyperpolarization was mediated by activation of sst receptors and required the function of G proteins. The SST-induced hyperpolarization resulted from decreased activity of AC and reduced levels of cAMP but did not require the activity of either PKA or PKC. Inhibition of Epac2, a guanine nucleotide exchange factor, partially blocked SST-mediated hyperpolarization of subicular neurons. Furthermore, application of SST resulted in a robust depression of subicular action potential firing and the SST-induced hyperpolarization was responsible for its inhibitory action on LTP at the CA1-subicilum synapses. Our results provide a novel cellular and molecular mechanism that may explain the roles of SST in modulation of subicular function and be relevant to SST-related physiological functions.