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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Paolo Tornese, Universita degli Studi di Milano
  • ,
  • Nathalie Sala, Universita degli Studi di Milano
  • ,
  • Daniela Bonini, University of Brescia
  • ,
  • Tiziana Bonifacino, Dipartimento di Pediatria, Università degli Studi di Genova, Genova, Italy.
  • ,
  • Luca La Via, University of Brescia
  • ,
  • Marco Milanese, Dipartimento di Pediatria, Università degli Studi di Genova, Genova, Italy.
  • ,
  • Giulia Treccani
  • Mara Seguini, Universita degli Studi di Milano
  • ,
  • Alessandro Ieraci, Universita degli Studi di Milano
  • ,
  • Jessica Mingardi, University of Brescia
  • ,
  • Jens R. Nyengaard
  • Stefano Calza, University of Brescia
  • ,
  • Giambattista Bonanno, Dipartimento di Pediatria, Università degli Studi di Genova, Genova, Italy.
  • ,
  • Gregers Wegener
  • Alessandro Barbon, University of Brescia
  • ,
  • Maurizio Popoli, Universita degli Studi di Milano
  • ,
  • Laura Musazzi, Universita degli Studi di Milano

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.

Original languageEnglish
Article number100160
JournalNeurobiology of Stress
Volume10
DOIs
Publication statusPublished - 2019

    Research areas

  • Antidepressant, BDNF, Chronic stress, Glutamate release, Ketamine, Stress vulnerability

See relations at Aarhus University Citationformats

ID: 152858908