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

Kiemes, A.; Serrano Navacerrada, M. E.; Kim, E.; Randall, K.; Simmons, C.; Rojo Gonzales, L.; Petrinovic, M.-M.; Lythgoe, D.; Rotaru, D.; Di Censo, D.; Hirschler, L.; Barbier, E.; Vernon, A. C.; Stone, J. M.; Davies, C.; Cash, D.; Modinos, G.

doi:10.1101/2022.03.07.483347

bioRxiv · 10.1101/2022.03.07.483347

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

Kiemes, A.·Serrano Navacerrada, M. E.·Kim, E.·Randall, K.·Simmons, C.·Rojo Gonzales, L.·Petrinovic, M.-M.·Lythgoe, D.·Rotaru, D.·Di Censo, D.·Hirschler, L.·Barbier, E.·Vernon, A. C.·Stone, J. M.·Davies, C.·Cash, D.·Modinos, G.

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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 5 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.

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Kiemes, A., Serrano Navacerrada, M. E., Kim, E., Randall, K., Simmons, C., Rojo Gonzales, L., Petrinovic, M.-M., Lythgoe, D., Rotaru, D., Di Censo, D., Hirschler, L., Barbier, E., Vernon, A. C., Stone, J. M., Davies, C., Cash, D., Modinos, G.. 2022-03-08. Erbb4 deletion from fast-spiking interneurons causes psychosis-relevant neuroimaging phenotypes. https://doi.org/10.1101/2022.03.07.483347

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