NPY y 1 receptors differentially modulate gaba a and nmda receptors via divergent signal-transduction pathways to reduce excitability of amygdala neurons

Andrei I. Molosh, Tammy J. Sajdyk, William Truitt, Weiguo Zhu, Gerry S. Oxford, Anantha Shekhar

Research output: Contribution to journalArticle

28 Citations (Scopus)

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-β-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 cAMP-dependent. 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 NMDA-mediated eEPSCs. This multipathway regulation of NMDA-and GABA A-mediated currents may be important for NPY plasticity and stress resilience in the amygdala.

Original languageEnglish
Pages (from-to)1352-1364
Number of pages13
JournalNeuropsychopharmacology
Volume38
Issue number7
DOIs
StatePublished - Jun 2013

Fingerprint

N-Methylaspartate
Amygdala
Signal Transduction
gamma-Aminobutyric Acid
Inhibitory Postsynaptic Potentials
Neurons
Neuropeptide Y
Cyclic AMP-Dependent Protein Kinases
GTP-Binding Proteins
GABA Agents
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Excitatory Postsynaptic Potentials
Anti-Anxiety Agents
Colforsin
neuropeptide Y-Y1 receptor
Synaptic Transmission
Catalytic Domain
Protein Isoforms
Proteins
Anxiety

Keywords

  • anxiety
  • Epac
  • neuromodulation
  • neuropeptide Y
  • PKA
  • stress

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Medicine(all)

Cite this

NPY y 1 receptors differentially modulate gaba a and nmda receptors via divergent signal-transduction pathways to reduce excitability of amygdala neurons. / Molosh, Andrei I.; Sajdyk, Tammy J.; Truitt, William; Zhu, Weiguo; Oxford, Gerry S.; Shekhar, Anantha.

In: Neuropsychopharmacology, Vol. 38, No. 7, 06.2013, p. 1352-1364.

Research output: Contribution to journalArticle

@article{feecf1afbde94b918cd1f95e51377262,
title = "NPY y 1 receptors differentially modulate gaba a 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-β-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 cAMP-dependent. 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 NMDA-mediated eEPSCs. This multipathway regulation of NMDA-and GABA A-mediated currents may be important for NPY plasticity and stress resilience in the amygdala.",
keywords = "anxiety, Epac, neuromodulation, neuropeptide Y, PKA, stress",
author = "Molosh, {Andrei I.} and Sajdyk, {Tammy J.} and William Truitt and Weiguo Zhu and Oxford, {Gerry S.} and Anantha Shekhar",
year = "2013",
month = "6",
doi = "10.1038/npp.2013.33",
language = "English",
volume = "38",
pages = "1352--1364",
journal = "Neuropsychopharmacology",
issn = "0893-133X",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - NPY y 1 receptors differentially modulate gaba a and nmda receptors via divergent signal-transduction pathways to reduce excitability of amygdala neurons

AU - Molosh, Andrei I.

AU - Sajdyk, Tammy J.

AU - Truitt, William

AU - Zhu, Weiguo

AU - Oxford, Gerry S.

AU - Shekhar, Anantha

PY - 2013/6

Y1 - 2013/6

N2 - 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-β-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 cAMP-dependent. 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 NMDA-mediated eEPSCs. This multipathway regulation of NMDA-and GABA A-mediated currents may be important for NPY plasticity and stress resilience in the amygdala.

AB - 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-β-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 cAMP-dependent. 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 NMDA-mediated eEPSCs. This multipathway regulation of NMDA-and GABA A-mediated currents may be important for NPY plasticity and stress resilience in the amygdala.

KW - anxiety

KW - Epac

KW - neuromodulation

KW - neuropeptide Y

KW - PKA

KW - stress

UR - http://www.scopus.com/inward/record.url?scp=84878554280&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878554280&partnerID=8YFLogxK

U2 - 10.1038/npp.2013.33

DO - 10.1038/npp.2013.33

M3 - Article

C2 - 23358240

AN - SCOPUS:84878554280

VL - 38

SP - 1352

EP - 1364

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

SN - 0893-133X

IS - 7

ER -