TrpV1 receptor activation rescues neuronal function and network gamma oscillations from Aβ-induced impairment in mouse hippocampus in vitro

Abstract

Amyloid-β peptide (Aβ) forms plaques in Alzheimer's Disease (AD) and is responsible for early cognitive deficits in AD patients. Advancing cognitive decline is accompanied by progressive impairment of cognition-relevant EEG patterns such as gamma oscillations. The endocannabinoid anandamide, a TrpV1-receptor agonist, reverses hippocampal damage and memory impairment in rodents and protects neurons from Aβ-induced cytotoxic effects. Here we investigate a restorative role of TrpV1-receptor activation against Aβ-induced degradation of hippocampal neuron function and gamma oscillations. We found that the TrpV1-receptor agonist capsaicin rescues Aβ-induced degradation of hippocampal gamma oscillations by reversing both the desynchronization of AP firing in CA3 pyramidal cells and the shift in excitatory/inhibitory current balance. This rescue effect is TrpV1-receptor-dependent since it was absent in TrpV1 knockout mice or in the presence of the TrpV1-receptor antagonist capsazepine. Our findings provide novel insight into the network mechanisms underlying cognitive decline in AD and suggest TrpV1 activation as a novel therapeutic target.

Data availability

Source data files have been provided for all figures, figure supplements, and the unitary action potential recordings.

Article and author information

Author details

  1. Hugo Balleza-Tapia

    Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3045-4594
  2. Sophie Crux

    Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  3. Yuniesky Andrade-Talavera

    Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  4. Pablo Dolz-Gaiton

    Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  5. Daniela Papadia

    Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  6. Gefei Chen

    Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  7. Jan Johansson

    Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  8. André Fisahn

    Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institute, Stockholm, Sweden
    For correspondence
    andre.fisahn@ki.se
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1480-175X

Funding

Vetenskapsrådet

  • André Fisahn

Alzheimerfonden

  • Jan Johansson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Experiments were performed in accordance with the ethical permit granted by Norra Stockholms Djurförsöksetiska Nämnd to AF (N45/13). Animals used in this study included p17-30 C57BL/6 (WT) and TrpV1 knockout (TrpV1 KO) male mice (Charles River Laboratories and Jackson Laboratory, respectively). Animals were deeply anesthetized using isoflurane before being sacrificed by decapitation.

Copyright

© 2018, Balleza-Tapia et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,292
    views
  • 395
    downloads
  • 63
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Hugo Balleza-Tapia
  2. Sophie Crux
  3. Yuniesky Andrade-Talavera
  4. Pablo Dolz-Gaiton
  5. Daniela Papadia
  6. Gefei Chen
  7. Jan Johansson
  8. André Fisahn
(2018)
TrpV1 receptor activation rescues neuronal function and network gamma oscillations from Aβ-induced impairment in mouse hippocampus in vitro
eLife 7:e37703.
https://doi.org/10.7554/eLife.37703

Share this article

https://doi.org/10.7554/eLife.37703

Further reading

    1. Neuroscience
    Andrea Brenna, Micaela Borsa ... Urs Albrecht
    Research Article

    The circadian clock enables organisms to synchronize biochemical and physiological processes over a 24 hr period. Natural changes in lighting conditions, as well as artificial disruptions like jet lag or shift work, can advance or delay the clock phase to align physiology with the environment. Within the suprachiasmatic nucleus (SCN) of the hypothalamus, circadian timekeeping and resetting rely on both membrane depolarization and intracellular second-messenger signaling. Voltage-gated calcium channels (VGCCs) facilitate calcium influx in both processes, activating intracellular signaling pathways that trigger Period (Per) gene expression. However, the precise mechanism by which these processes are concertedly gated remains unknown. Our study in mice demonstrates that cyclin-dependent kinase 5 (Cdk5) activity is modulated by light and regulates phase shifts of the circadian clock. We observed that knocking down Cdk5 in the SCN of mice affects phase delays but not phase advances. This is linked to uncontrolled calcium influx into SCN neurons and an unregulated protein kinase A (PKA)-calcium/calmodulin-dependent kinase (CaMK)-cAMP response element-binding protein (CREB) signaling pathway. Consequently, genes such as Per1 are not induced by light in the SCN of Cdk5 knock-down mice. Our experiments identified Cdk5 as a crucial light-modulated kinase that influences rapid clock phase adaptation. This finding elucidates how light responsiveness and clock phase coordination adapt activity onset to seasonal changes, jet lag, and shift work.

    1. Neuroscience
    Moritz F Wurm, Doruk Yiğit Erigüç
    Research Article

    Recognizing goal-directed actions is a computationally challenging task, requiring not only the visual analysis of body movements, but also analysis of how these movements causally impact, and thereby induce a change in, those objects targeted by an action. We tested the hypothesis that the analysis of body movements and the effects they induce relies on distinct neural representations in superior and anterior inferior parietal lobe (SPL and aIPL). In four fMRI sessions, participants observed videos of actions (e.g. breaking stick, squashing plastic bottle) along with corresponding point-light-display (PLD) stick figures, pantomimes, and abstract animations of agent–object interactions (e.g. dividing or compressing a circle). Cross-decoding between actions and animations revealed that aIPL encodes abstract representations of action effect structures independent of motion and object identity. By contrast, cross-decoding between actions and PLDs revealed that SPL is disproportionally tuned to body movements independent of visible interactions with objects. Lateral occipitotemporal cortex (LOTC) was sensitive to both action effects and body movements. These results demonstrate that parietal cortex and LOTC are tuned to physical action features, such as how body parts move in space relative to each other and how body parts interact with objects to induce a change (e.g. in position or shape/configuration). The high level of abstraction revealed by cross-decoding suggests a general neural code supporting mechanical reasoning about how entities interact with, and have effects on, each other.