Temporal dynamics of BDNF signaling recruitment in the rat prefrontal cortex and hippocampus following a single infusion of a translational dose of ketamine

Lucia Caffino; Francesca Mottarlini; Alessandro Piva; Beatrice Rizzi; Fabio Fumagalli; Cristiano Chiamulera

doi:10.1016/j.neuropharm.2023.109767

Temporal dynamics of BDNF signaling recruitment in the rat prefrontal cortex and hippocampus following a single infusion of a translational dose of ketamine

Lucia Caffino, Francesca Mottarlini, Alessandro Piva, Beatrice Rizzi, Fabio Fumagalli, Cristiano Chiamulera

Neuropharmacology October 17, 2023 DOI: 10.1016/j.neuropharm.2023.109767 (opens in new tab)

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Study at a glance

AI-extracted from the abstract

Characteristics	Preclinical animal study Peer reviewed
Population	Male Sprague-Dawley rats
Intervention	Ketamine
Duration	First 24 h after infusion
Topics	Esketamine Ketamine
Citations	14
Key points	Slow ketamine infusion activated the BDNF-mTOR-S6 pathway in rat prefrontal cortex from 2 to at least 6 hours after infusion; at 12 hours the pathway was off in prefrontal cortex but activated in hippocampus, and at 24 hours it appeared activated in both regions through a BDNF-independent mechanism. The authors present these as previously unknown temporal dynamics of ketamine's early effects.

Abstract

Despite several decades of investigations, the mechanisms underlying the rapid action of ketamine as antidepressant are still far from being completely understood. Several studies indicated Brain-Derived Neurotrophic Factor (BDNF) as critical for the fast antidepressant action of ketamine, due to its contribution in early and rapid synaptic adaptations. However, previous reports have been essentially based on ketamine dosing modes that differ from the clinical route of administration (slow intravenous infusion). In this report, we investigated the effects of a ketamine dosing mode in male Sprague-Dawley rats showed to be translational to the clinically effective mode in patients. We focused on the first 24 h after infusion to finely dissect potential differences in the contribution of BDNF signaling pathway in prefrontal cortex and hippocampus, two brain regions involved in the antidepressant effects of ketamine. Our data show that the slow ketamine infusion activates the BDNF-mTOR-S6 pathway in prefrontal cortex as early as 2 h and remains on until at least 6 h after the infusion. At the 12 h timepoint, this pathway is turned off in prefrontal cortex while it becomes activated in hippocampus. Interestingly, this pathway appears to be activated in both brain regions at 24 h through a BDNF-independent mechanism adding complexity to the early action of ketamine. We have captured previously unknown dynamics of the early effects of ketamine showing rapid activation/deactivation of BDNF and its downstream signaling in prefrontal cortex and hippocampus, following a precise temporal profile.

Comparable studies

Other preclinical and animal studies on ketamine, most cited first.

Study	Year	Design
mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats	2010	Observational study
Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats	1997	Dose-response study with microdialysis and behavioral testing
NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice	2016	Preclinical study
The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats	1983	Experimental study
R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice	2015	Experimental study

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