NPY2 Receptors Reduce Tonic Action Potential-Independent GABAB 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 Y2R 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, Y2R-sensitive GABA(B)R currents were action potential-independent, persisting after treatment with TTX. Additionally, the Ca2+ -dependent, slow afterhyperpolarizing K+ current (I-sAHP) was enhanced in approximately half of the Y2R-sensitive PNs, possibly from enhanced Ca2+ influx, permitted by reduced GABA B R tone. In male and female mice expressing tdTomato in Y2R-mRNA cells (tdT-Y2R mice), immunohistochemistry revealed that BLA somatostatin interneurons express Y(2)Rs, as do a significant subset of BLA PNs. In tdT-Y2R mice, [ahx(5-24)]NPY increased excitability and suppressed the K-IR in nearly all BLA PNs independent of tdT-Y2R fluorescence, consistent with presynaptic Y(2)Rs on somatostatin interneurons mediating the above effects. However, only tdT-Y2R-expressing PNs responded to [ahx(5-24)]NPY with an enhancement of the I-sAHP. Ultimately, increased PN excitability via acute Y2R activation likely correlates with enhanced BLA output, consistent with reported Y2R-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.