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

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.

Investigating brain alterations in the Dp1Tyb mouse model of Down syndrome

“…The individual spectra were acquired using a Point rEsolved Spectroscopy (PRESS) pulse sequence ( Yahya, 2009 ) with the following parameters: TE = 8.26 ms, TR = 2500 ms, 512 averages, acquisition bandwidth = 4401 Hz, 2048 acquisition points, voxel size = 2.2 × 1.2 × 2.5 mm. Outer volume suppression and water suppression with variable pulse power and optimized relaxation delays (VAPOR) were used in order to mitigate the contribution of signal from outside the prescribed voxel and suppress unwanted signal from water, as described by ( Kiemes et al, 2022 ).…”

“…The MR spectra obtained from each animal were analysed with two software packages: FID Appliance (FID-A) ( Simpson et al, 2017 ) and Linear Combination (LC) Model version 6.3 ( Provencher, 1993 , 2001 ). In total, eleven metabolites were quantified, as per ( Kiemes et al, 2022 ): creatine (Cr), gamma-aminobutyric acid (GABA), glutamine (Gln), glutamate (Glu), glutathione (GSH), myo -inositol (Ins), lactate (Lac), N -acetyl-aspartate (NAA), phosphocholine (PCh) phosphocreatine (PCr), and taurine (Taur).…”

Investigating Brain Alterations in the Dp1Tyb Mouse Model of Down Syndrome

“…The MR spectra obtained from each animal were analysed with two software packages: FID Appliance (FID-A) (Simpson et al, 2017) and Linear Combination (LC) Model version 6.3 (Provencher, 1993(Provencher, , 2001. In total, eleven metabolites were quantified, as per (Kiemes et al, 2022): creatine (Cr), gamma-aminobutyric acid (GABA), glutamine (Gln), glutamate (Glu), glutathione (GSH), myo-inositol (Ins), lactate (Lac), Nacetyl-aspartate (NAA), phosphocholine (PCh) phosphocreatine (PCr), and taurine (Taur).…”