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

Although NPY has potent anxiolytic actions within the BLA, selective activation of BLA NPY Y 2 receptors (Y 2 Rs) acutely increases anxiety by an unknown mechanism. Using ex vivo male rat brain slice electrophysiology, we show that the selective Y 2 R agonist, [ahx 5-24 ]NPY, reduced the frequency of GABA A -mediated mIPSCs in BLA principal neurons (PNs). [ahx 5-24 ]NPY also reduced tonic activation of GABA B receptors (GABA B R), which increased PN excitability through inhibition of a tonic, inwardly rectifying potassium current ( K IR ). Surprisingly, Y 2 R-sensitive GABA B R currents were action potential-independent, persisting after treatment with TTX. Additionally, the Ca 2+ -dependent, slow afterhyperpolarizing K + current ( I sAHP ) was enhanced in approximately half of the Y 2 R-sensitive PNs, possibly from enhanced Ca 2+ influx, permitted by reduced GABA B R tone. In male and female mice expressing tdTomato in Y 2 R-mRNA cells (tdT-Y 2 R mice), immunohistochemistry revealed that BLA somatostatin interneurons express Y 2 Rs, as do a significant subset of BLA PNs. In tdT-Y 2 R mice, [ahx 5-24 ]NPY increased excitability and suppressed the K IR in nearly all BLA PNs independent of tdT-Y 2 R fluorescence, consistent with presynaptic Y 2 Rs on somatostatin interneurons mediating the above effects. However, only tdT-Y 2 R-expressing PNs responded to [ahx 5-24 ]NPY with an enhancement of the I sAHP Ultimately, increased PN excitability via acute Y 2 R activation likely correlates with enhanced BLA output, consistent with reported Y 2 R-mediated anxiogenesis. Furthermore, we demonstrate the following: (1) a novel mechanism whereby activity-independent GABA release can powerfully dampen BLA neuronal excitability via postsynaptic GABA B Rs; and (2) that this tonic inhibition can be interrupted by neuromodulation, here by NPY via Y 2 Rs. SIGNIFICANCE STATEMENT Within the BLA, NPY is potently anxiolytic. However, selective activation of NPY 2 receptors (Y 2 Rs) increases anxiety by an unknown mechanism. We show that activation of BLA Y 2 Rs decreases tonic GABA release onto BLA principal neurons, probably from Y 2 R-expressing somatostatin interneurons, some of which coexpress NPY. This increases principal neuron excitability by reducing GABA B receptor (GABA B R)-mediated activation of G-protein-coupled, inwardly rectifying K + currents. Tonic, Y 2 R-sensitive GABA B R currents unexpectedly persisted in the absence of action potential firing, revealing, to our knowledge, the first report of substantial, activity-independent GABA B R activation. Ultimately, we provide a plausible explanation for Y 2 R-mediated anxiogenesis in vivo and describe a novel and modulatable means of damping neuronal excitability.

(Copyright © 2019 the authors.)