NPY2 Receptors Reduce Tonic Action Potential-Independent GABAB Currents in the Basolateral Amygdala

• Published in: The Journal of neuroscience 2019-06, Vol.39 (25), p.4909-4930
• Main Authors: Mackay, James P, Bompolaki, Maria, DeJoseph, M Regina, Michaelson, Sheldon D, Urban, Janice H, Colmers, William F
• Format: Article
• Language: English
• Subjects: Action potential; Activation; Amygdala; Anxiety; Brain; Brain slice preparation; Calcium influx; Calcium ions; DNA nucleotidylexotransferase; Electrophysiology; Excitability; Fluorescence; Immunohistochemistry; Inhibition; Interneurons; Mice; mRNA; Neuromodulation; Neuropeptide Y; Neuropeptide Y2 receptors; Potassium; Receptors; Rodents; Somatostatin; γ-Aminobutyric acid A receptors; γ-Aminobutyric acid B receptors
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.2226-18.2019

Although NPY has potent anxiolytic actions within the BLA, selective activation of BLA NPY Y2 receptors (Y2Rs) acutely increases anxiety by an unknown mechanism. Using ex vivo male rat brain slice electrophysiology, we show that the selective Y2R agonist, [ahx5–24]NPY, reduced the frequency of GABAA-mediated mIPSCs in BLA principal neurons (PNs). [ahx5–24]NPY also reduced tonic activation of GABAB receptors (GABABR), which increased PN excitability through inhibition of a tonic, inwardly rectifying potassium current (KIR). Surprisingly, Y2R-sensitive GABABR currents were action potential-independent, persisting after treatment with TTX. Additionally, the Ca2+-dependent, slow afterhyperpolarizing K+ current (IsAHP) was enhanced in approximately half of the Y2R-sensitive PNs, possibly from enhanced Ca2+ influx, permitted by reduced GABABR tone. In male and female mice expressing tdTomato in Y2R-mRNA cells (tdT-Y2R mice), immunohistochemistry revealed that BLA somatostatin interneurons express Y2Rs, as do a significant subset of BLA PNs. In tdT-Y2R mice, [ahx5–24]NPY increased excitability and suppressed the KIR in nearly all BLA PNs independent of tdT-Y2R fluorescence, consistent with presynaptic Y2Rs on somatostatin interneurons mediating the above effects. However, only tdT-Y2R-expressing PNs responded to [ahx5–24]NPY with an enhancement of the IsAHP. 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 GABABRs; and (2) that this tonic inhibition can be interrupted by neuromodulation, here by NPY via Y2Rs.