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

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.

Effects of Repeated Stress on Age-Dependent GABAergic Regulation of the Lateral Nucleus of the Amygdala

“…For instance, increased excitatory responses to glutamate and increased glutamatergic synaptic transmission. The increased excitatory response to glutamate could be caused by increased neuronal membrane excitability (Rosenkranz et al, 2010;Hetzel and Rosenkranz, 2014), increased function of NMDA or AMPA receptors (Adamec et al, 2005;Caudal et al, 2010;Mozhui et al, 2010;Suvrathan et al, 2014), reduced glutamatergic drive of GABAergic networks (Masneuf et al, 2014), or upregulation of glutamatergic receptors (Lei and Tejani-Butt, 2010;Gan et al, 2014). Increased glutamatergic synaptic transmission could be caused by increased glutamatergic inputs, as observed here and in other studies (Mitra et al, 2005;Vyas et al, 2006;Padival et al, 2013Padival et al, , 2015Suvrathan et al, 2014;Tsai et al, 2014).…”

General and emotion-specific neural effects of ketamine during emotional memory formation

“…Recent animal work emphasizes an involvement of NMDAR-dependent signalling in medial prefrontal cortex (mPFC) and amygdala during emotional processing and emotion-cognition interactions, including emotional learning (Vieira et al, 2015;Hegoburu et al, 2014;Masneuf et al, 2014). These are in line with studies in humans which revealed emotion-specific disruptions during facial emotion encoding and recognition, as well as altered amygdala and prefrontal functioning following ketamine-induced NMDAR blockade (Ebert et al, 2012;Schmidt et al, 2013, Abel et al, 2003.…”

Simvastatin treatment reduces the cholesterol content of membrane/lipid rafts, implicating the N -methyl-D-aspartate receptor in anxiety: a literature review

“…The results of a number of studies performed in recent years indicate that glutamatergic neurotransmission Simvastatin → Farnesyl Pyrophosphate ↓ → H-Ras ↓ → NMDA receptor ↑ via ionotropic receptors is involved in the pathophysiology of anxiety (Masneuf et al, 2014). The ionotropic glutamate receptor family comprises ligand-gated channels divided into three groups named after their selective agonists, namely NMDA, AMPA, and kainate and their density is high in cortical and limbic regions implicated in the mediation of fear and anxiety (Bergink, van Megen, Westenberg, 2004;Réus et al, 2015).…”

“…Modulation of NMDA receptors activity after SIM treatment could explain the drug's anxiolytic-like effects (Camargo et al, 2013;Carrocini et al, 2012;Cruz et al, 2011;Kilic et al, 2012;Pauleti et al, 2013;Santos et al, 2012;Wang et al, 2009;Yan et al, 2011). This hypothesis could be supported by the fact that altered levels of NMDA receptors in the hippocampus and amygdala directly influence anxiety behaviors (Barkus et al, 2010;Blundell, Adamec, 2007;Masneuf et al, 2014).…”