Glutamatergic mechanisms associated with stress-induced amygdala excitability and anxiety-related behavior

Sophie Masneuf, Emily Lowery-Gionta, Giovanni Colacicco, Kristen E. Pleil, Chia Li, Nicole Crowley, Shaun Flynn, Andrew Holmes, Thomas Kash

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29 Scopus citations

Abstract

The neural factors underlying individual differences in susceptibility to chronic stress remain poorly understood. Preclinical studies demonstrate that mouse strains vary greatly in anxiety-related responses to chronic stress in a manner paralleled by differential stress-induced changes in glutamatergic signaling in the basolateral amygdala (BLA). Previous work has also shown that alterations in the amygdala gene expression of the GluN1 NMDA and the GluK1 kainate receptors are associated with stress-induced alterations in anxiety-like behavior in the C57BL/6J mouse strain. Using in vivo behavioral pharmacological and ex vivo physiological approaches, the aim of the current study was to further elucidate changes in glutamate neurotransmission in the BLA caused by stress and to test the functional roles of GluN1 and GluK1 in mediating stress-related changes in behavior. Results showed that stress-induced alterations in anxiety-like behavior (light/dark exploration test) were absent following bilateral infusion of the GluK1 agonist ATPA into the BLA. Intra-BLA infusion of the competitive NMDA antagonist AP5 produced a generalized behavioral disinhibition/locomotor hyperactivity, irrespective of stress. Slice electrophysiological recordings showed that ATPA augmented BLA GABAergic neurotransmission and that stress increased the amplitude of network-dependent spontaneous excitatory postsynaptic currents and amplitude of GABAergic miniature inhibitory postsynaptic currents in BLA. These findings could indicate stress-induced BLA glutamatergic neuronal network hyperexcitability and a compensatory increase in GABAergic neurotransmission, suggesting that GluK1 agonism augmented GABAergic inhibition to prevent behavioral sequelae of stress. Current data could have implications for developing novel therapeutic approaches, including GluK1 agonists, for stress-related anxiety disorders.

Original languageEnglish (US)
Pages (from-to)190-197
Number of pages8
JournalNeuropharmacology
Volume85
DOIs
StatePublished - Oct 2014

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cellular and Molecular Neuroscience

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    Masneuf, S., Lowery-Gionta, E., Colacicco, G., Pleil, K. E., Li, C., Crowley, N., Flynn, S., Holmes, A., & Kash, T. (2014). Glutamatergic mechanisms associated with stress-induced amygdala excitability and anxiety-related behavior. Neuropharmacology, 85, 190-197. https://doi.org/10.1016/j.neuropharm.2014.04.015