Neurobiology of Depression: Chronic Stress Alters the Glutamatergic System in the Brain—Focusing on AMPA Receptor

Abstract

Major depressive disorder (MDD) is a common neuropsychiatric disorder affecting the mood and mental well-being. Its pathophysiology remains elusive due to the complexity and heterogeneity of this disorder that affects millions of individuals worldwide. Chronic stress is frequently cited as the one of the risk factors for MDD. To date, the conventional monoaminergic theory (serotonin, norepinephrine, and/or dopamine dysregulation) has received the most attention in the treatment of MDD, and all available classes of antidepressants target these monoaminergic systems. However, the contributions of other neurotransmitter systems in MDD have been widely reported. Emerging preclinical and clinical findings reveal that maladaptive glutamatergic neurotransmission might underlie the pathophysiology of MDD, thus revealing its critical role in the neurobiology of MDD and as the therapeutic target. Aiming beyond the monoaminergic hypothesis, studies of the neurobiological mechanisms underlying the stress-induced impairment of AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-glutamatergic neurotransmission in the brain could provide novel insights for the development of a new generation of antidepressants without the detrimental side effects. Here, the authors reviewed the recent literature focusing on the role of AMPA-glutamatergic neurotransmission in stress-induced maladaptive responses in emotional and mood-associated brain regions, including the hippocampus, amygdala, prefrontal cortex, nucleus accumbens and periaqueductal gray.

Effects of the acute administration of delta-opioid receptor ligands on the excitability of rat hippocampal glutamate and brainstem monoamine neurons in vivo

“…The hippocampal neurons investigated by Moravcikova and colleagues were presumably pyramidal glutamatergic ones, as it was assumed from their morphology and characteristic ion currents across the membrane. Since hippocampal glutamate transmission is involved in antidepressant drugs response (Hlavacova et al 2018;Lee et al 2022), it is possible that anxiolytic and antidepressant-like effects of SNC80, observed in previous studies, are explained, at least in part, via the ability of this ligand to modulate the firing activity of hippocampal neurons. To test this hypothesis, the effect of SNC80, as well as of the selective DOR antagonist naltrindole, on the excitability of hippocampal glutamate neurons, should be tested in in vivo conditions.…”

Dysfunctional serotonergic neuron-astrocyte signaling in depressive-like states

“…It has been reported that depressive-like states disrupt excitatory synaptic transmission and synaptic plasticity [ 107 ]. Synaptic transmission and plasticity are tightly regulated by serotonergic signaling [ 108 ], which is related to important physiological processes, such as sleep, body temperature, appetite, pain and motor activity [ 109 ].…”

Depression, an unmet health need in Africa: Understanding the promise of ketamine

“…Studies reporting increased levels of glutamate in the prefrontal cortex of individuals who have committed suicide, suggesting dysregulation in glutamate and GABA excitation/inhibition signalling. Subsequently a glutamatergic theory has been formulated to explain the development of depression [ 14 , [10] , [15] , [16] ]. The neuroinflammatory theory proposes chronic exposure to inflammatory mediators to trigger the development of depression, where inflammation is believed to drive many of the neurodegenerative processes observed in depression [ [17] , [18] , [19] ].…”