1. Neuroscience

Auditory mismatch responses are differentially sensitive to changes in muscarinic acetylcholine versus dopamine receptor function

  1. Lilian Aline Weber  Is a corresponding author
  2. Sara Tomiello
  3. Dario Schöbi
  4. Katharina V. Wellstein
  5. Daniel Mueller
  6. Sandra Iglesias
  7. Klaas Enno Stephan
  1. University of Zurich, Switzerland
  2. University Hospital of Zurich, Switzerland
https://doi.org/10.7554/eLife.74835
Share this article
Cite this article
  1. Lilian Aline Weber
  2. Sara Tomiello
  3. Dario Schöbi
  4. Katharina V. Wellstein
  5. Daniel Mueller
  6. Sandra Iglesias
  7. Klaas Enno Stephan
(2022)
Auditory mismatch responses are differentially sensitive to changes in muscarinic acetylcholine versus dopamine receptor function
eLife 11:e74835.
https://doi.org/10.7554/eLife.74835
  2. Download BibTeX
  3. Download .RIS

Abstract

The auditory mismatch negativity (MMN) has been proposed as a biomarker of NMDA receptor (NMDAR) dysfunction in schizophrenia. Such dysfunction may be caused by aberrant interactions of different neuromodulators with NMDARs, which could explain clinical heterogeneity among patients. In two studies (N=81 each), we used a double-blind placebo-controlled between-subject design to systematically test whether auditory mismatch responses under varying levels of environmental stability are sensitive to diminishing and enhancing cholinergic vs. dopaminergic function. We found a significant drug x mismatch interaction: while the muscarinic acetylcholine receptor antagonist biperiden delayed and topographically shifted mismatch responses, particularly during high stability, this effect could not be detected for amisulpride, a dopamine D2/D3 receptor antagonist. Neither galantamine nor levodopa, which elevate acetylcholine and dopamine levels, respectively, exerted significant effects on MMN. This differential MMN sensitivity to muscarinic versus dopaminergic receptor function may prove useful for developing tests that predict individual treatment responses in schizophrenia.

Data availability

All raw data (EEG data, behavior) used for this manuscript are available at https://research-collection.ethz.ch/handle/20.500.11850/477685, adhering to the FAIR (Findable, Accessible, Interoperable, and Re-usable) data principles. The analysis code that reproduces the results presented here is publicly available on the GIT repository of ETH Zurich at https://gitlab.ethz.ch/tnu/code/weber-muscarinic-mmn-erp-2021.

The following data sets were generated

Article and author information

Author details

  1. Lilian Aline Weber

    Translational Neuroimaging Unit (TNU), Institute for Biomedical EngineeringInstitute for Biomedical Engineering, University of Zurich, Zurich, Switzerland
    For correspondence
    weber@biomed.ee.ethz.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9727-9623

  2. Sara Tomiello

    Translational Neuroimaging Unit (TNU), Institute for Biomedical Engineering, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  3. Dario Schöbi

    Translational Neuroimaging Unit (TNU), Institute for Biomedical Engineering, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  4. Katharina V. Wellstein

    Translational Neuroimaging Unit (TNU), Institute for Biomedical Engineering, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  5. Daniel Mueller

    Institute for Clinical Chemistry, University Hospital of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  6. Sandra Iglesias

    Translational Neuroimaging Unit (TNU), Institute for Biomedical Engineering, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1778-7239

  7. Klaas Enno Stephan

    Translational Neuroimaging Unit (TNU), Institute for Biomedical Engineering, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8594-9092

Funding

University of Zurich (N/A)

  • Klaas Enno Stephan

René und Susanne Braginsky Stiftung (N/A)

  • Klaas Enno Stephan

Max Planck Institute for Metabolism Research (open access funding)

  • Klaas Enno Stephan

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

Ethics

Human subjects: All participants gave written informed consent prior to data acquisition and were financially reimbursed for their participation. The study was approved by the cantonal Ethics Committee of Zurich (KEK-ZH-Nr. 2011-0101/3).

Copyright

© 2022, Weber 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

  • 1,310
    views
  • 198
    downloads
  • 10
    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. Lilian Aline Weber
  2. Sara Tomiello
  3. Dario Schöbi
  4. Katharina V. Wellstein
  5. Daniel Mueller
  6. Sandra Iglesias
  7. Klaas Enno Stephan
(2022)
Auditory mismatch responses are differentially sensitive to changes in muscarinic acetylcholine versus dopamine receptor function
eLife 11:e74835.
https://doi.org/10.7554/eLife.74835

Share this article

https://doi.org/10.7554/eLife.74835

Categories and tags

Research organism

Further reading

    1. Neuroscience

    Sequential replacement of PSD95 subunits in postsynaptic supercomplexes is slowest in the cortex

    Katie Morris, Edita Bulovaite ... Mathew H Horrocks
    Research Article

    The concept that dimeric protein complexes in synapses can sequentially replace their subunits has been a cornerstone of Francis Crick’s 1984 hypothesis, explaining how long-term memories could be maintained in the face of short protein lifetimes. However, it is unknown whether the subunits of protein complexes that mediate memory are sequentially replaced in the brain and if this process is linked to protein lifetime. We address these issues by focusing on supercomplexes assembled by the abundant postsynaptic scaffolding protein PSD95, which plays a crucial role in memory. We used single-molecule detection, super-resolution microscopy and MINFLUX to probe the molecular composition of PSD95 supercomplexes in mice carrying genetically encoded HaloTags, eGFP, and mEoS2. We found a population of PSD95-containing supercomplexes comprised of two copies of PSD95, with a dominant 12.7 nm separation. Time-stamping of PSD95 subunits in vivo revealed that each PSD95 subunit was sequentially replaced over days and weeks. Comparison of brain regions showed subunit replacement was slowest in the cortex, where PSD95 protein lifetime is longest. Our findings reveal that protein supercomplexes within the postsynaptic density can be maintained by gradual replacement of individual subunits providing a mechanism for stable maintenance of their organization. Moreover, we extend Crick’s model by suggesting that synapses with slow subunit replacement of protein supercomplexes and long-protein lifetimes are specialized for long-term memory storage and that these synapses are highly enriched in superficial layers of the cortex where long-term memories are stored.

    1. Medicine
    2. Neuroscience

    NE contribution to rebooting unconsciousness caused by midazolam

    LeYuan Gu, WeiHui Shao ... HongHai Zhang
    Research Article

    The advent of midazolam holds profound implications for modern clinical practice. The hypnotic and sedative effects of midazolam afford it broad clinical applicability. However, the specific mechanisms underlying the modulation of altered consciousness by midazolam remain elusive. Herein, using pharmacology, optogenetics, chemogenetics, fiber photometry, and gene knockdown, this in vivo research revealed the role of locus coeruleus (LC)-ventrolateral preoptic nucleus noradrenergic neural circuit in regulating midazolam-induced altered consciousness. This effect was mediated by α1 adrenergic receptors. Moreover, gamma-aminobutyric acid receptor type A (GABAA-R) represents a mechanistically crucial binding site in the LC for midazolam. These findings will provide novel insights into the neural circuit mechanisms underlying the recovery of consciousness after midazolam administration and will help guide the timing of clinical dosing and propose effective intervention targets for timely recovery from midazolam-induced loss of consciousness.

    1. Neuroscience

    The gamma rhythm as a guardian of brain health

    Ana Maria Ichim, Harald Barzan ... Raul Cristian Muresan
    Review Article

    Gamma oscillations in brain activity (30–150 Hz) have been studied for over 80 years. Although in the past three decades significant progress has been made to try to understand their functional role, a definitive answer regarding their causal implication in perception, cognition, and behavior still lies ahead of us. Here, we first review the basic neural mechanisms that give rise to gamma oscillations and then focus on two main pillars of exploration. The first pillar examines the major theories regarding their functional role in information processing in the brain, also highlighting critical viewpoints. The second pillar reviews a novel research direction that proposes a therapeutic role for gamma oscillations, namely the gamma entrainment using sensory stimulation (GENUS). We extensively discuss both the positive findings and the issues regarding reproducibility of GENUS. Going beyond the functional and therapeutic role of gamma, we propose a third pillar of exploration, where gamma, generated endogenously by cortical circuits, is essential for maintenance of healthy circuit function. We propose that four classes of interneurons, namely those expressing parvalbumin (PV), vasointestinal peptide (VIP), somatostatin (SST), and nitric oxide synthase (NOS) take advantage of endogenous gamma to perform active vasomotor control that maintains homeostasis in the neuronal tissue. According to this hypothesis, which we call GAMER (GAmma MEdiated ciRcuit maintenance), gamma oscillations act as a ‘servicing’ rhythm that enables efficient translation of neural activity into vascular responses that are essential for optimal neurometabolic processes. GAMER is an extension of GENUS, where endogenous rather than entrained gamma plays a fundamental role. Finally, we propose several critical experiments to test the GAMER hypothesis.