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Erbb4 deletion from fast-spiking interneurons causes psychosis-relevant neuroimaging phenotypes

View ORCID ProfileA. Kiemes, View ORCID ProfileM. E. Serrano Navacerrada, View ORCID ProfileE. Kim, K. Randall, View ORCID ProfileC. Simmons, L. Rojo Gonzalez, View ORCID ProfileM.M. Petrinovic, View ORCID ProfileD.J. Lythgoe, View ORCID ProfileD. Rotaru, D. Di Censo, View ORCID ProfileL. Hirshler, View ORCID ProfileE. L. Barbier, View ORCID ProfileA. C. Vernon, View ORCID ProfileJ. M. Stone, View ORCID ProfileC. Davies, View ORCID ProfileD. Cash, View ORCID ProfileG. Modinos
doi: https://doi.org/10.1101/2022.03.07.483347
A. Kiemes
1Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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  • For correspondence: amanda.s.kiemes@kcl.ac.uk
M. E. Serrano Navacerrada
2Department of Neuroimaging, School of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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E. Kim
2Department of Neuroimaging, School of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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K. Randall
2Department of Neuroimaging, School of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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C. Simmons
2Department of Neuroimaging, School of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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L. Rojo Gonzalez
2Department of Neuroimaging, School of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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M.M. Petrinovic
3MRC Centre for Neurodevelopmental Disorders, King’s College London, London, UK
4Department of Forensic and Neurodevelopmental Science, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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D.J. Lythgoe
2Department of Neuroimaging, School of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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D. Rotaru
2Department of Neuroimaging, School of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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D. Di Censo
2Department of Neuroimaging, School of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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L. Hirshler
5C.J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, Netherlands; Department of Radiology, Leiden University Medical Center, Leiden, Netherlands
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E. L. Barbier
6Grenoble Institut des Neurosciences, Inserm, Univ. Grenoble Alpes, Grenoble, France
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A. C. Vernon
3MRC Centre for Neurodevelopmental Disorders, King’s College London, London, UK
7Department of Basic and Clinical Neuroscience, School of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, UK
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J. M. Stone
8Brighton and Sussex Medical School, University of Sussex, Brighton, UK
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C. Davies
1Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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D. Cash
2Department of Neuroimaging, School of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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G. Modinos
1Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
2Department of Neuroimaging, School of Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
3MRC Centre for Neurodevelopmental Disorders, King’s College London, London, UK
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Abstract

Converging lines of evidence suggest that dysfunction of cortical parvalbumin-expressing (PV+) GABAergic interneurons is a core feature of psychosis. This dysfunction is thought to underlie neuroimaging abnormalities commonly found in patients with psychosis, particularly in the hippocampus. These include increases in resting cerebral blood flow (CBF) and levels of glutamatergic metabolites, and decreases in binding of GABAA α5 receptors and the synaptic density marker synaptic vesicle glycoprotein 2A (SV2A). However, direct links between PV+ interneuron dysfunction and these neuroimaging readouts have yet to be established. Conditional deletion of a schizophrenia susceptibility gene, the tyrosine kinase receptor Erbb4, from cortical and hippocampal PV+ interneurons leads to several synaptic, behavioral and cognitive phenotypes relevant to psychosis in mice. Here, we investigated how this PV+ interneuron disruption affects the hippocampal in vivo neuroimaging readouts in the Erbb4 model. Adult Erbb4 conditional mutant mice (Lhx6-Cre;Erbb4F/F, n=12) and their wild-type littermates (Erbb4F/F, n=12) were scanned in a 9.4T magnetic resonance scanner to quantify CBF and glutamatergic metabolite levels (glutamine, glutamate, GABA). Subsequently, we assessed GABAA receptors and SV2A density using quantitative autoradiography. Erbb4 mutant mice showed significantly elevated CBF and glutamine levels, as well as decreased SV2A density compared to wild-type littermates. No significant GABAA receptor density differences were identified. These findings demonstrate that specific disruption of cortical PV+ interneurons in mice recapitulate some of the key neuroimaging findings in psychosis patients, and link PV+ interneuron deficits to non-invasive, translational measures of brain function and neurochemistry that can be used across species.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted March 08, 2022.
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Erbb4 deletion from fast-spiking interneurons causes psychosis-relevant neuroimaging phenotypes
A. Kiemes, M. E. Serrano Navacerrada, E. Kim, K. Randall, C. Simmons, L. Rojo Gonzalez, M.M. Petrinovic, D.J. Lythgoe, D. Rotaru, D. Di Censo, L. Hirshler, E. L. Barbier, A. C. Vernon, J. M. Stone, C. Davies, D. Cash, G. Modinos
bioRxiv 2022.03.07.483347; doi: https://doi.org/10.1101/2022.03.07.483347
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Erbb4 deletion from fast-spiking interneurons causes psychosis-relevant neuroimaging phenotypes
A. Kiemes, M. E. Serrano Navacerrada, E. Kim, K. Randall, C. Simmons, L. Rojo Gonzalez, M.M. Petrinovic, D.J. Lythgoe, D. Rotaru, D. Di Censo, L. Hirshler, E. L. Barbier, A. C. Vernon, J. M. Stone, C. Davies, D. Cash, G. Modinos
bioRxiv 2022.03.07.483347; doi: https://doi.org/10.1101/2022.03.07.483347

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