Linking Hypothermia and Altered Metabolism with TrkB Activation

Okko Alitalo; Gemma González-Hernández; Marko Rosenholm; Piia Kohtala; Nobuaki Matsui; Heidi Kaastrup Müller; Wiebke Theilmann; Anders Klein; Olli Kärkkäinen; Stanislav Rozov; Tomi Rantamäki; Samuel Kohtala

doi:10.1021/acschemneuro.3c00350

Linking Hypothermia and Altered Metabolism with TrkB Activation

Okko Alitalo, Gemma González-Hernández, Marko Rosenholm, Piia Kohtala, Nobuaki Matsui, Heidi Kaastrup Müller, Wiebke Theilmann, Anders Klein, Olli Kärkkäinen, Stanislav Rozov, Tomi Rantamäki^*, Samuel Kohtala^*

^*Corresponding author for this work

Department of Clinical Medicine - Translational Neuropsychiatry Unit

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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Abstract

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.

Original language	English
Journal	ACS Chemical Neuroscience
Volume	14
Issue	17
Pages (from-to)	3212-3225
Number of pages	14
ISSN	1948-7193
DOIs	https://doi.org/10.1021/acschemneuro.3c00350
Publication status	Published - Sept 2023

Keywords

antidepressant
energy metabolism
hypothermia
neuroplasticity
physiology
rapid-acting antidepressant
sedation
sleep deprivation

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title = "Linking Hypothermia and Altered Metabolism with TrkB Activation",

abstract = "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.",

keywords = "antidepressant, energy metabolism, hypothermia, neuroplasticity, physiology, rapid-acting antidepressant, sedation, sleep deprivation",

author = "Okko Alitalo and Gemma Gonz{\'a}lez-Hern{\'a}ndez and Marko Rosenholm and Piia Kohtala and Nobuaki Matsui and M{\"u}ller, {Heidi Kaastrup} and Wiebke Theilmann and Anders Klein and Olli K{\"a}rkk{\"a}inen and Stanislav Rozov and Tomi Rantam{\"a}ki and Samuel Kohtala",

year = "2023",

month = sep,

doi = "10.1021/acschemneuro.3c00350",

language = "English",

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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

PY - 2023/9

Y1 - 2023/9

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

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DO - 10.1021/acschemneuro.3c00350

M3 - Journal article

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AN - SCOPUS:85168462419

SN - 1948-7193

VL - 14

SP - 3212

EP - 3225

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

IS - 17

ER -

Linking Hypothermia and Altered Metabolism with TrkB Activation

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