Chronic mild stress induces anhedonic behavior and changes in glutamate release, BDNF trafficking and dendrite morphology only in stress vulnerable rats. The rapid restorative action of ketamine

Abstract

Depression is a debilitating mental disease, characterized by persistent low mood and anhedonia. Stress represents a major environmental risk factor for depression; the complex interaction of stress with genetic factors results in different individual vulnerability or resilience to the disorder. Dysfunctions of the glutamate system have a primary role in depression. Clinical neuroimaging studies have consistently reported alterations in volume and connectivity of cortico-limbic areas, where glutamate neurons and synapses predominate. This is confirmed by preclinical studies in rodents, showing that repeated stress induces morphological and functional maladaptive changes in the same brain regions altered in humans. Confirming the key role of glutamatergic transmission in depression, compelling evidence has shown that the non-competitive NMDA receptor antagonist, ketamine, induces, at sub-anesthetic dose, rapid and sustained antidepressant response in both humans and rodents. We show here that the Chronic Mild Stress model of depression induces, only in stress-vulnerable rats, depressed-like anhedonic behavior, together with impairment of glutamate/GABA presynaptic release, BDNF mRNA trafficking in dendrites and dendritic morphology in hippocampus. Moreover, we show that a single administration of ketamine restores, in 24 h, normal behavior and most of the cellular/molecular maladaptive changes in vulnerable rats. Interestingly, ketamine treatment did not restore BDNF mRNA levels reduced by chronic stress but rescued dendritic trafficking of BDNF mRNA. The present results are consistent with a mechanism of ketamine involving rapid restoration of synaptic homeostasis, through re-equilibration of glutamate/GABA release and dendritic BDNF for synaptic translation and reversal of synaptic and circuitry impairment.

Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers

“…In rats vulnerable to chronic mild stress, ketamine was noted to result in reversal of anhedonic behavior, partial attenuation of hippocampal impairments in presynaptic release of glutamate and GABA, along with complete restoration of dendritic atrophy and dendritic BDNF mRNA trafficking. 108 In a mouse model of social defeat stress, ketamine was noted to attenuate reductions in BDNF, dendritic spine density, GluA1 and PSD-95 (both markers of synaptogenesis) in the PFC, dentate gyrus and CA3 region of the hippocampus at 8 days following drug administration. 109 In an investigation employing two-photon imaging in the PFC of living mice exposed to chronic stress, ketamine rescued elimination of postsynaptic dendritic spines and reversed the loss of coordinated activity of multicellular ensembles in projection neurons.…”

Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites

“…It has also been reported that the regulation of glutamate transporter 1 on astrocytes through the activation of TrkB is involved in the beneficial effects of ketamine on behavioral abnormalities and morphological changes in the hippocampus of chronic unpredictable mild stress (CUMS)-exposed rats 88 . A recent study showed that ketamine restores depression-like phenotypes in CUMS-exposed vulnerable rats by rescuing the dendritic trafficking of Bdnf mRNA 89 . In addition, the ketamine-induced regulation of TrkB is independent of HNK 90 .…”

BDNF Val66Met polymorphism alters food intake and hypothalamic BDNF expression in mice

“…Brain‐derived neurotrophic factor (BDNF) is a member of the neurotrophin family, which plays a central role in neurogenesis, differentiation, survival, and synaptic plasticity (Leal, Bramham, & Duarte, 2017; Numakawa, Odaka, & Adachi, 2018; Tornese et al, 2019). BDNF is also an anorexigenic factor that regulates food intake, body weight, and metabolism.…”