NPY 2 Receptors Reduce Tonic Action Potential-Independent GABA B Currents in the Basolateral Amygdala.

Although neuropeptide Y (NPY) has potent anxiolytic actions within the basolateral amygdala (BLA), selective activation of BLA NPY Y2 receptors (Y2 R) acutely increases anxiety by an unknown mechanism. Using ex vivo male rat brain slice electrophysiology, we show that the selective Y2 R agonist, [ahx5-24 ]NPY, reduced the frequency of GABAA -mediated miniature inhibitory post synaptic currents (mIPSC) in BLA principal neurons (PN). [ahx5-24 ]NPY also reduced tonic activation of GABAB receptors (GABAB R), which increased PN excitability through inhibition of a tonic, inwardly-rectifying potassium current ( KIR ). Surprisingly, Y2 R-sensitive GABAB R currents were action potential-independent, persisting after treatment with tetrodotoxin. Additionally, the Ca2+ -dependent, slow afterhyperpolarizing K+ current ( IsAHP ) was enhanced in roughly half of the Y2 R-sensitive PNs, possibly from enhanced Ca2+ influx, permitted by reduced GABAB R tone. In male and female mice expressing tdTomato in Y2 R-expressing cells (tdT-Y2 R mice), immunohistochemistry revealed that BLA somatostatin interneurons (SST IN) express Y2 Rs, as do a significant subset of BLA PNs. In tdT-Y2 R mice, [ahx5-24 ]NPY increased excitability and suppressed the KIR in nearly all BLA PNs independent of tdT-Y2 R fluorescence, consistent with presynaptic Y2 Rs on SST INs mediating the above effects. However, only tdT-Y2 R-expressing PNs responded to [ahx5-24 ]NPY with an enhancement of the IsAHP Ultimately, increased PN excitability via acute Y2 R activation likely correlates with enhanced BLA output, consistent with reported Y2 R-mediated anxiogenesis. Furthermore, we demonstrate: 1) a novel mechanism whereby activity-independent GABA release can powerfully dampen BLA neuronal excitability via postsynaptic GABAB Rs, and 2) that this tonic inhibition can be interrupted by neuromodulation, here by NPY via Y2 Rs. SIGNIFICANCE STATEMENT Within the basolateral amygdala (BLA), neuropeptide Y (NPY) is potently anxiolytic. However, selective activation of NPY2 -receptors (Y2 R) increases anxiety by an unknown mechanism. We show that activation of BLA Y2 Rs decreases tonic GABA release onto BLA principal neurons (PN), probably from Y2 R-expressing somatostatin interneurons some of which co-express NPY. This increases PN excitability by reducing GABAB receptor (GABAB R)-mediated activation of G-protein-coupled, inwardly-rectifying K+ (GIRK) currents. Tonic, Y2 R- sensitive GABAB R currents unexpectedly persisted in the absence of action potential firing, revealing, to our knowledge, the first report of substantial, activity-independent GABAB R activation. Ultimately, we provide a plausible explanation for Y2 R-mediated anxiogenesis in vivo and describe a novel and modulatable means of damping neuronal excitability.