The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission

Abstract

Preface Mounting evidence suggests that acute and chronic stress, especially the stress-induced release of glucocorticoids, induces changes in glutamate neurotransmission in the prefrontal cortex and the hippocampus, thereby influencing some aspects of cognitive processing. In addition, dysfunction of glutamatergic neurotransmission is increasingly considered to be a core feature of stress-related mental illnesses. Recent studies have shed light on the mechanisms by which stress and glucocorticoids affect glutamate transmission, including effects on glutamate release, glutamate receptors and glutamate clearance and metabolism. This new understanding provides insights into normal brain functioning as well as the pathophysiology and potential new treatments of stress-related neuropsychiatric disorders.

Hypothalamic CNTF volume transmission shapes cortical noradrenergic excitability upon acute stress

“…Therefore, secondary response pathways to enable an individual's prolonged vigilance might have evolved to confer added evolutionary benefit when responding to recurrent challenges. Seminal studies (Schulkin et al , 1994; McEwen & Sapolsky, 1995; Popoli et al , 2011) support this notion by documenting that corticosteroids released from the adrenals do not only produce feedback inhibition of hypothalamic and pituitary hormone secretion (Akana et al , 1992) but directly regulate limbic and reward circuits (Sapolsky, 2003) to gate coping and flexibility (e.g., “flight or fight” behaviors; Eriksen et al , 1999; McEwen et al , 2012), motivation (McEwen, 2005), memory (Roozendaal et al , 2009), and fear extinction (Korte, 2001; McEwen, 2005). The prefrontal cortex (PFC) has emerged as a central site to orchestrate coordinated responses to acute stress (McEwen, 2007) with glucocorticoid and mineralocorticoid receptors modulating its ability to integrate upstream emotional, sensory, cognitive, and spatial inputs (Patel et al , 2008; Gadek‐Michalska et al , 2013; Caudal et al , 2014).…”

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

“…Learned helplessness in rats is a widely-used behavioral model of depression. The underlying mechanism is associated with a marked increase in depolarization-evoked glutamate release in the PFC, which can be mitigated by monoaminebased antidepressants [44][45][46] . Moreover, antidepressants reduce the release of glutamate, possibly by decreasing phospho-activation of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) [47] .…”

“…Prior to this, the conceptual framework of depression was dominated by the monoaminergic hypothesis, so most of the antidepressants developed for clinical therapy target monoaminergic transmission. However, s tress affects glutamate release, cl earance, metabolism, receptor function, and receptor expression, strongly implicating glutamatergic transmission and plasticity in the pathogenesis of depression [46] . Glutamate signaling is mediated by both ionotropic (AMPARs and NMDARs) and metabotropic glutamate receptors (mGluR1 to mGluR8).…”

“…However, s tress affects glutamate release, cl earance, metabolism, receptor function, and receptor expression, strongly implicating glutamatergic transmission and plasticity in the pathogenesis of depression [46] . Glutamate signaling is mediated by both ionotropic (AMPARs and NMDARs) and metabotropic glutamate receptors (mGluR1 to mGluR8).Excitatory synaptic efficacy is determined by the singlechannel conductance, the number, and the stability of glutamate receptors at the postsynaptic membrane [46] .Acute stress enhances glutamate transmission by increasing the surface expression of NMDARs and AMPARs at the postsynaptic membrane, which dynamically regulates metaplasticity (e.g., LTP/LTD induction thresholds) at glutamatergic synapses [105] . Chronic stress further alters glutamatergic circuits and the survival of ne wborn glutamatergic neurons [106,107] .…”

“…Thus, disturbed glutamatergic neurotransmission is likely a core feature of stress-related mental illnesses. Drugs influencing basal transmission, plasticity, and metaplasticity may be effective antidepressants that act rapidly [46,108,109] . …”