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

Samuel Kohtala,Leena Penna,Ipek Yalcin,Salla Uusitalo,Kaija Järventausta,Tomi Rantamäki,Marko Rosenholm,Nobuaki Matsui,Henna-Kaisa Wigren,Gulsum Karabulut,Arvi Yli-Hankala,Wiebke Theilmann

doi:10.1007/s12035-018-1364-6

Abstract

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

Highlights

Major depression is a highly disabling condition, the most significant risk factor for suicide and one of the biggest contributors to the global disease burden [1]
We focused our analyses to the medial prefrontal cortex, a brain region associated in the pathophysiology of depression and antidepressant actions
And as previously shown, subanesthetic ketamine and flurothyl evoked slow EEG oscillations that were generated after the peak of pharmacological effects had already passed

Summary

Introduction

Major depression is a highly disabling condition, the most significant risk factor for suicide and one of the biggest contributors to the global disease burden [1]. Many patients respond poorly to standard antidepressants, and with those who do respond, the therapeutic effects become evident with a considerable delay. Experimental evidence suggests that ketamine increases glutamate release and enhances glutamatergic AMPA-R (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) function, which in turn augments synaptic plasticity through the BDNF (brain-derived neurotrophic factor) receptor TrkB [5,6,7,8,9,10]. Positive allosteric AMPA-R modulators increase BDNF synthesis in the brain and produce antidepressant-like effects in rodents [11]. Inhibition of GSK3β (glycogen synthase kinase 3β), another molecular event tightly connected with ketamine’s therapeutic effects [12], contributes to the enhanced AMPA-R function [13]

Methods

Results

Conclusion