NPY Y1 Receptors Differentially Modulate GABAA and NMDA Receptors via Divergent Signal-Transduction Pathways to Reduce Excitability of Amygdala Neurons

Abstract

Neuropeptide Y (NPY) administration into the basolateral amygdala (BLA) decreases anxiety-like behavior, mediated in part through the Y 1 receptor (Y 1 R) isoform. Activation of Y 1 Rs results in G-protein-mediated reduction of cAMP levels, which results in reduced excitability of amygdala projection neurons. Understanding the mechanisms linking decreased cAMP levels to reduced excitability in amygdala neurons is important for identifying novel anxiolytic targets. We studied the intracellular mechanisms of activation of Y 1 Rs on synaptic transmission in the BLA. Activating Y 1 Rs by [Leu 31 ,Pro 34 ]-NPY (L-P NPY) reduced the amplitude of evoked NMDA-mediated excitatory postsynaptic currents (eEPSCs), without affecting AMPA-mediated eEPSCs, but conversely increased the amplitude of GABA A -mediated evoked inhibitory postsynaptic currents (eIPSCs). Both effects were abolished by the Y 1 R antagonist, PD160170. Intracellular GDP-b-S, or pre-treatment with either forskolin or 8Br-cAMP, eliminated the effects of L-P NPY on both NMDA-and GABA A -mediated currents. Thus, both the NMDA and GABA A effects of Y 1 R activation in the BLA are G-protein-mediated and cAMPdependent. Pipette inclusion of protein kinase A (PKA) catalytic subunit blocked the effect of L-P NPY on GABA A -mediated eIPSCs, but not on NMDA-mediated eEPSCs. Conversely, activating the exchange protein activated by cAMP (Epac) with 8CPT-2Me-cAMP blocked the effect of L-P NPY on NMDA-mediated eEPSCs, but not on GABA A -mediated eIPSCs. Thus, NPY regulates amygdala excitability via two signal-transduction events, with reduced PKA activity enhancing GABA A -mediated eIPSCs and Epac deactivation reducing NMDAmediated eEPSCs. This multipathway regulation of NMDA-and GABA A -mediated currents may be important for NPY plasticity and stress resilience in the amygdala.

Melanocortin-4 receptor–regulated energy homeostasis

“…Indeed, in Npy −/− mice ARC AgRP →PVH GABAergic synaptic strength is potentiated, indicating some level of compensatory developmental rewiring 9 . In a developed neural system, however, pharmacological blockade of GABA or NPY signaling specifically in the PVH (at GABA A receptors and Y1 receptors, respectively) independently abolishes optogenetic ARC AgRP →PVH–driven feeding 9 , implying that both systems are required, and potentially cooperate 37 , to inhibit satiety-promoting PVH neurons. Unlike the rapid or exigenic effect of centrally infused NPY, AgRP administration is effective only after a number of hours 38 .…”

The role of Neuropeptide Y in fear conditioning and extinction

“…Specifically, activation of Gi/o-coupled Y1 receptors reduces NMDA receptor-mediated excitatory postsynaptic currents and increases GABA A receptormediated inhibitory postsynaptic currents by reducing the activity of exchange protein activated by cAMP (Epac) and Protein Kinase A (PKA), respectively (Molosh et al, 2013). It is worth highlighting that the Y1 receptor was also found to increase GABA A receptormediated inhibition in the BNST (Pleil et al, 2015), as this provides a fine example of the similarities in Y receptor function in different brain regions.…”

Altered neurotransmission in the lateral amygdala in aged human apoE4 targeted replacement mice

“…It is also involved in the regulation of neural processes that influence affective states such as depression and anxiety, which commonly occur in AD (Molosh et al, 2013). For example, Hamann et al (2002) found significant impairment in fear conditioning in AD patients, suggesting a loss of synaptic integrity in the amygdala.…”