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Cited by 18Neural dynamics and brain functionGenetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology Research

Neurexin1α knockout rats display oscillatory abnormalities and sensory processing deficits back-translating key endophenotypes of psychiatric disorders

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Janz, Philipp, Bainier, Marie, Marashli, Samuel, Schoenenberger, Philipp, Valencia, Miguel, Redondo, Roger L.·2022·Translational Psychiatry
DOI 10.1038/s41398-022-02224-1PMC PMC9616904
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Abstract

Neurexins are presynaptic transmembrane proteins crucial for synapse development and organization. Deletion and missense mutations in all three Neurexin genes have been identified in psychiatric disorders, with mutations in the NRXN1 gene most strongly linked to schizophrenia (SZ) and autism spectrum disorder (ASD). While the consequences of NRXN1 deletion have been extensively studied on the synaptic and behavioral levels, circuit endophenotypes that translate to the human condition have not been characterized yet. Therefore, we investigated the electrophysiology of cortico-striatal-thalamic circuits in Nrxn1α−/−rats and wildtype littermates focusing on a set of translational readouts, including spontaneous oscillatory activity, auditory-evoked oscillations and potentials, as well as mismatch negativity-like (MMN) responses and responses to social stimuli. On the behavioral level Nrxn1α−/−rats showed locomotor hyperactivity. In vivo freely moving electrophysiology revealed pronounced increases of spontaneous oscillatory power within the gamma band in all studied brain areas and elevation of gamma coherence in cortico-striatal and thalamocortical circuits of Nrxn1α−/−rats. In contrast, auditory-evoked oscillations driven by chirp-modulated tones showed reduced power in cortical areas confined to slower oscillations. Finally, Nrxn1α−/−rats exhibited altered auditory evoked-potentials and profound deficits in MMN-like responses, explained by reduced prediction error. Despite deficits for auditory stimuli, responses to social stimuli appeared intact. A central hypothesis for psychiatric and neurodevelopmental disorders is that a disbalance of excitation-to-inhibition is underlying oscillatory and sensory deficits. In a first attempt to explore the impact of inhibitory circuit modulation, we assessed the effects of enhancing tonic inhibition via δ-containing GABA A receptors (using Gaboxadol) on endophenotypes possibly associated with network hyperexcitability. Pharmacological experiments applying Gaboxadol showed genotype-specific differences, but failed to normalize oscillatory or sensory processing abnormalities. In conclusion, our study revealed endophenotypes in Nrxn1α−/−rats that could be used as translational biomarkers for drug development in psychiatric disorders.

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  • Janz et al. (2022) reported hyperactivity, deficits in context-dependent auditory processing but a normal response towards social stimuli in nrxn1-deficient rats.

    “Janz et al. (2022) reported hyperactivity, deficits in context-dependent auditory processing but a normal response towards social stimuli.”

    From Neurexin1α knockout in rats causes aberrant social behaviour: relevance for autism and schizophrenia (2025) · cites this paper as Janz et al. (2022)

    The Results report locomotor hyperactivity and severe deficits in context-dependent auditory processing in Nrxn1α−/− rats. In “Intact responses to social stimuli” (page not provided), the paper describes social stimulus-driven responses as overall intact, but notes subtle attenuation of beta-band oscillatory power; calling the response simply normal omits that qualification. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Janz, P., Bainier, M., Marashli, S., Schoenenberger, P., Valencia, M., & Redondo, R. L.
Affiliations
  • F. Hoffmann-La Roche AG (CH)
  • Navarre Institute of Health Research (ES)
Corresponding author
Janz, Philipp
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2022-10-28
Volume
12
Issue
1
Pages
455-455
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-022-02224-1
PMC
PMC9616904
OpenAlex
W4307476003
Cited by
18
References
6
Citations by year
2026: 2 · 2025: 3 · 2024: 11 · 2023: 2
FWCI
2.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
endophenotypes, schizophrenia, autism spectrum disorder, spontaneous oscillations, gamma oscillations, gamma coherence, auditory evoked potentials, mismatch negativity, prediction error, social behavior, locomotor hyperactivity, excitation-inhibition balance, tonic inhibition, GABAA receptor, gaboxadol, translational biomarkers
MeSH terms
Autism Spectrum Disorder, Animals, Mental Disorders, Electroencephalography, Evoked Potentials, Auditory, Humans, Perception, Rats, Endophenotypes

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