Biology subjects

Kohtala, P.

Publications and source records attributed to Kohtala, P..

3 recordsLinked to original sources

bioRxiv2025

Nitrous oxide modulates cortical activity, wake-sleep oscillations, and produces antidepressant-like effects in mice

Emerging evidence suggests that nitrous oxide (N2O), a gaseous NMDA receptor antagonist and dissociative anesthetic, exerts rapid antidepressant effects akin to subanesthetic ketamine. However, its cellular, molecular, and behavioral effects remain poorly understood. Using in vivo two-photon imaging through cortical microprisms, we demonstrate that 50% N2O/O2 rapidly increases neuronal calcium activity in the mouse medial prefrontal cortex (mPFC). This was corroborated by elevated c-Fos expression at both protein and mRNA levels in mPFC lysates. Cortical EEG recordings revealed that N2O increased subsequent wake-associated gamma oscillations and enhanced slow-wave activity during sleep, suggestive of cortical activation and synaptic potentiation. In a chronic corticosterone stress model, N2O elicited antidepressant-like behavioral effects in several, though not all, domains. Together, these findings indicate that a single treatment with N2O rapidly enhances cortical activity, modulates sleep and wake EEG oscillations, and produces antidepressant-like effects, paralleling key actions associated with subanesthetic ketamine.

neuroscience↗

bioRxiv2023

Synaptic plasticity via receptor tyrosine kinase / G protein-coupled receptor crosstalk

Cellular signaling involves a large repertoire of membrane receptors operating in overlapping spatiotemporal regimes and targeting many common intracellular effectors. However, both the molecular mechanisms and physiological roles of crosstalk between receptors, especially those from different superfamilies, are poorly understood. We find that the receptor tyrosine kinase (RTK), TrkB, and the G protein-coupled receptor (GPCR), metabotropic glutamate receptor 5 (mGluR5), together mediate a novel form of hippocampal synaptic plasticity in response to brain-derived neurotrophic factor (BDNF). Activated TrkB enhances constitutive mGluR5 activity to initiate a mode-switch that drives BDNF-dependent sustained, oscillatory Ca2+ signaling and enhanced MAP kinase activation. This crosstalk is mediated, in part, by synergy between G{beta}{gamma}, released by TrkB, and Gq-GTP, released by mGluR5, to enable a previously unidentified form of physiologically relevant RTK/GPCR crosstalk.

cell biology↗

bioRxiv2021

Physiological basis underlying antidepressant-induced activation of TrkB receptors

We show that both pharmacological and non-pharmacological treatments of depression activate TrkB receptors--a well-established target of antidepressants--by inducing a physiological response coupled to sedation. Several rapid-acting antidepressants trigger TrkB signaling by evoking a state associated with electroencephalographic slow-wave activity, behavioral immobility, reduced cerebral glucose utilization, and lowered body temperature. Remarkably, antidepressant-induced TrkB signaling was not compromised in animals exhibiting reduced activity-dependent release of BDNF but was diminished by maintaining animals in warm ambient temperature. Most importantly, prevention of the hypothermic response attenuated the behavioral effects produced by rapid-acting antidepressant nitrous oxide. Our results suggest that the phenomenon underlying TrkB transactivation--changes in energy expenditure and thermoregulation--is essential, but not sufficient, for antidepressant responses. Indeed, regardless of differential clinical and pharmacodynamic properties, all drugs that disrupt energy metabolism and induce hypothermia activated TrkB. This study challenges pharmacology-centric hypotheses regarding antidepressant effects and highlight the role of complex changes in bioenergetics and thermoregulation. HighlightsO_LIRapid-acting antidepressants evoke homeostatic emergence of slow-wave sleep during which TrkB signaling becomes regulated. C_LIO_LINon-antidepressant metabolic inhibitors and diverse sedatives activate TrkB signaling. C_LIO_LIReduction in body temperature determined the ability of antidepressants to transactivate TrkB. C_LIO_LIDrug-induced TrkB signaling was blunted by maintenance of normothermic body temperature. C_LIO_LIWarm ambient temperature after nitrous oxide exposure blocked the antidepressant-like effects. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/458151v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1f7351borg.highwire.dtl.DTLVardef@bf920forg.highwire.dtl.DTLVardef@10e34eaorg.highwire.dtl.DTLVardef@1b42bb6_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗