TY - JOUR

T1 - Linking Hypothermia and Altered Metabolism with TrkB Activation

AU - Alitalo, Okko

AU - González-Hernández, Gemma

AU - Rosenholm, Marko

AU - Kohtala, Piia

AU - Matsui, Nobuaki

AU - Müller, Heidi Kaastrup

AU - Theilmann, Wiebke

AU - Klein, Anders

AU - Kärkkäinen, Olli

AU - Rozov, Stanislav

AU - Rantamäki, Tomi

AU - Kohtala, Samuel

N1 - Publisher Copyright: © 2023 The Authors. Published by American Chemical Society.

PY - 2023

Y1 - 2023

N2 - Many mechanisms have been proposed to explain acute antidepressant drug-induced activation of TrkB neurotrophin receptors, but several questions remain. In a series of pharmacological experiments, we observed that TrkB activation induced by antidepressants and several other drugs correlated with sedation, and most importantly, coinciding hypothermia. Untargeted metabolomics of pharmacologically dissimilar TrkB activating treatments revealed effects on shared bioenergetic targets involved in adenosine triphosphate (ATP) breakdown and synthesis, demonstrating a common perturbation in metabolic activity. Both activation of TrkB signaling and hypothermia were recapitulated by administration of inhibitors of glucose and lipid metabolism, supporting a close relationship between metabolic inhibition and neurotrophic signaling. Drug-induced TrkB phosphorylation was independent of electroencephalography slow-wave activity and remained unaltered in knock-in mice with the brain-derived neurotrophic factor (BDNF) Val66Met allele, which have impaired activity-dependent BDNF release, alluding to an activation mechanism independent from BDNF and neuronal activity. Instead, we demonstrated that the active maintenance of body temperature prevents activation of TrkB and other targets associated with antidepressants, including p70S6 kinase downstream of the mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3β (GSK3β). Increased TrkB, GSK3β, and p70S6K phosphorylation was also observed during recovery sleep following sleep deprivation, when a physiological temperature drop is known to occur. Our results suggest that the changes in bioenergetics and thermoregulation are causally connected to TrkB activation and may act as physiological regulators of signaling processes involved in neuronal plasticity.

AB - Many mechanisms have been proposed to explain acute antidepressant drug-induced activation of TrkB neurotrophin receptors, but several questions remain. In a series of pharmacological experiments, we observed that TrkB activation induced by antidepressants and several other drugs correlated with sedation, and most importantly, coinciding hypothermia. Untargeted metabolomics of pharmacologically dissimilar TrkB activating treatments revealed effects on shared bioenergetic targets involved in adenosine triphosphate (ATP) breakdown and synthesis, demonstrating a common perturbation in metabolic activity. Both activation of TrkB signaling and hypothermia were recapitulated by administration of inhibitors of glucose and lipid metabolism, supporting a close relationship between metabolic inhibition and neurotrophic signaling. Drug-induced TrkB phosphorylation was independent of electroencephalography slow-wave activity and remained unaltered in knock-in mice with the brain-derived neurotrophic factor (BDNF) Val66Met allele, which have impaired activity-dependent BDNF release, alluding to an activation mechanism independent from BDNF and neuronal activity. Instead, we demonstrated that the active maintenance of body temperature prevents activation of TrkB and other targets associated with antidepressants, including p70S6 kinase downstream of the mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3β (GSK3β). Increased TrkB, GSK3β, and p70S6K phosphorylation was also observed during recovery sleep following sleep deprivation, when a physiological temperature drop is known to occur. Our results suggest that the changes in bioenergetics and thermoregulation are causally connected to TrkB activation and may act as physiological regulators of signaling processes involved in neuronal plasticity.

KW - antidepressant

KW - energy metabolism

KW - hypothermia

KW - neuroplasticity

KW - physiology

KW - rapid-acting antidepressant

KW - sedation

KW - sleep deprivation

U2 - 10.1021/acschemneuro.3c00350

DO - 10.1021/acschemneuro.3c00350

M3 - Journal article

C2 - 37551888

AN - SCOPUS:85168462419

VL - 14

SP - 3212

EP - 3225

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

IS - 17

ER -