Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses

• DOI: 10.1007/s12035-018-1364-6
• Publication Date: 2018-10-04T12:51:26Z
• Authors: Samuel Kohtala; Wiebke Theilmann; Marko Rosenholm; Leena Penna; Gulsum Karabulut; Salla Uusitalo; Kaija Järventausta; Arvi Yli-Hankala; Ipek Yalcin; Nobuaki Matsui; Henna-Kaisa Wigren; Tomi Rantamäki
• Keywords: STIMULATION; 0301 basic medicine; Nitrous Oxide; PREFRONTAL CORTEX; Article; Neurology and psychiatry; ELECTROCONVULSIVE-THERAPY; 03 medical and health sciences; NMDA RECEPTOR BLOCKADE; Neurologia ja psykiatria - Neurology and psychiatry; 616; Flurothyl; Animals; Homeostasis; Receptor, trkB; Rapid-acting antidepressant; Anesthetics; Cerebral Cortex; Neurons; 0303 health sciences; Nitrous oxide; Glycogen Synthase Kinase 3 beta; Dose-Response Relationship, Drug; DELTA-EEG; KETAMINE; Cortical excitation; NITROUS-OXIDE; Electroencephalography; GLYCOGEN-SYNTHASE KINASE-3; Medetomidine; Antidepressive Agents; Up-Regulation; 3. Good health; NEUROTROPHIN RECEPTOR; [SDV] Life Sciences [q-bio]; Mice, Inbred C57BL; Biomedicine; Electroencephalogram; Sedation; Ketamine; SLEEP-DEPRIVATION; Biomarkers; Farmasia - Pharmacy; Signal Transduction

Rapid antidepressant effects of ketamine become most evident when its psychotomimetic subside, but the neurobiological basis this "lag" remains unclear. Laughing gas (N2O), another NMDA-R (N-methyl-d-aspartate receptor) blocker, has been reported to bring rapidly upon drug discontinuation. We took advantage exceptional pharmacokinetic properties N2O investigate EEG (electroencephalogram) alterations and molecular determinants actions during immediately after blockade. Effects drugs on brain activity were investigated in C57BL/6 mice using quantitative recordings. Western blot qPCR used for analyses. Learned helplessness (LH) was assess antidepressant-like behavior. Immediate-early genes (e.g., bdnf) phosphorylation mitogen-activated protein kinase—markers neuronal excitability—were upregulated exposure. Notably, BDNF receptor TrkB GSK3β (glycogen synthase kinase 3β) became regulated only gradually discontinuation, a state dominated by slow activity. Subanesthetic flurothyl-induced convulsions (reminiscent electroconvulsive therapy) also evoked oscillations their acute pharmacological subsided. The correlation between ongoing TrkB-GSK3β signaling further strengthened utilizing medetomidine, hypnotic-sedative agent that facilitates directly through activation α2-adrenergic autoreceptors. Medetomidine did not, however, facilitate markers excitability or produce behavioral changes LH. Our results support hypothesis transient cortical subsequent regulation homeostatic emergence are critical components rapid responses.