Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 May 3;49(3):569-580.
doi: 10.1093/schbul/sbac192.

Erbb4 Deletion From Inhibitory Interneurons Causes Psychosis-Relevant Neuroimaging Phenotypes

Amanda Kiemes  1 , Maria Elisa Serrano Navacerrada  2 , Eugene Kim  2 , Karen Randall  2 , Camilla Simmons  2 , Loreto Rojo Gonzalez  2 , Marija-Magdalena Petrinovic  3   4 , David J Lythgoe  2 , Diana Rotaru  2 , Davide Di Censo  2   5 , Lydiane Hirschler  6   7 , Emmanuel L Barbier  7 , Anthony C Vernon  3   8 , James M Stone  9 , Cathy Davies  1 , Diana Cash  2 , Gemma Modinos  1   2   3
Affiliations

Erbb4 Deletion From Inhibitory Interneurons Causes Psychosis-Relevant Neuroimaging Phenotypes

Amanda Kiemes et al. Schizophr Bull. .

Abstract

Background and hypothesis: Converging lines of evidence suggest that dysfunction of cortical GABAergic inhibitory 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 glutamatergic metabolite levels, and decreases in ligand binding to GABAA α5 receptors and to the synaptic density marker synaptic vesicle glycoprotein 2A (SV2A). However, direct links between inhibitory interneuron dysfunction and these neuroimaging readouts are yet to be established. Conditional deletion of a schizophrenia susceptibility gene, the tyrosine kinase receptor Erbb4, from cortical and hippocampal inhibitory interneurons leads to synaptic defects, and behavioral and cognitive phenotypes relevant to psychosis in mice.

Study design: Here, we investigated how this inhibitory interneuron disruption affects hippocampal in vivo neuroimaging readouts. 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.

Results: Erbb4 mutant mice showed significantly elevated ventral hippccampus CBF and glutamine levels, and decreased SV2A density across hippocampus sub-regions compared to wild-type littermates. No significant GABAA receptor density differences were identified.

Conclusions: These findings demonstrate that specific disruption of cortical inhibitory interneurons in mice recapitulate some of the key neuroimaging findings in patients with psychosis, and link inhibitory interneuron deficits to non-invasive measures of brain function and neurochemistry that can be used across species.

Keywords: Erbb4; hippocampus; inhibitory interneurons; mice; neuroimaging; psychosis.

PubMed Disclaimer

Conflict of interest statement

In the last 3 years, JMS has been principal investigator or sub-investigator on studies sponsored by Takeda, Janssen, and Lundbeck Plc. He has attended an Investigators’ meeting run by Allergan Plc. All other authors have declared that there are no conflicts of interest in relation to the subject of this study.

Figures

Fig. 1.
Fig. 1.
Regional CBF in Lhx6-Cre;Erbb4F/F mice is increased in the ventral hippocampus. (A) Hippocampal regions of interest overlaid on a standard mouse brain template (approximate distance from Bregma, top −2.8, bottom −3.2); yellow (top) = dorsal hippocampus, orange (bottom) = ventral hippocampus. (B) Greater CBF in the ventral (Pcorr = 0.03, d = 0.80), but not dorsal hippocampus (Pcorr > 0.9, d = 0.21) of Lhx6-Cre;Erbb4F/F mutants (n = 12, 9 female, 3 male) compared to control mice (n = 10, 4 female, 6 male). vHip: ventral hippocampus; dHip: dorsal hippocampus.
Fig. 2.
Fig. 2.
(A) Representative 1H-MRS PRESS voxel (red; inner rectangle) and corresponding shim (green; outer rectangle) placement in ventral hippocampus (left) and 1H-MRS spectrum (right). (B) Z-scores of 1H-MRS metabolites in the ventral hippocampus. Glutamine was significantly higher in Lhx6-Cre;Erbb4F/F mutant mice (n = 12, 9 female, 3 male) compared to control mice (n = 12, 5 female, 7 male; Pcorr < .001, d = 1.96). GABA: gamma-aminobutyric acid; Glu: glutamate; Gln: glutamine.
Fig. 3.
Fig. 3.
Representative hippocampal regions of interests for quantitative autoradiography. (A) Regions of interests sampled for [3H]Ro15-4513 and [3H]flumazenil. (B) Regions of interests sampled for [3H]UCB-J. dHip CA1: dorsal hippocampus CA1; mHip CA3: middle hippocampus CA3; mHip CA1/2: middle hippocampus CA1/CA2; vHip CA3: ventral hippocampus CA3; dHip DG: dorsal hippocampus dentate gyrus; mHip DG: middle hippocampus dentate gyrus.
Fig. 4.
Fig. 4.
SV2A density, but not α5GABAAR or α1-3;5GABAAR, is decreased in Lhx6-Cre;Erbb4F/F mice across the hippocampus. (A) [3H]UCB-J autoradiography showed a significant decrease in binding in Lhx6-Cre;Erbb4F/F mice (n = 11, 8 female, 3 male) compared to control animals (n = 9, 3 female, 6 male) across all hippocampal ROIs (P = .02, η2 = 0.29). (B) [3H]Ro15-4513 (Erbb4F/Fn = 11, 5 female, 6 male; Lhx6;Erbb4F/Fn = 10, 7 female, 3 male) or (C) [3H]flumazenil (Erbb4F/Fn = 10, 4 female, 6 male; Lhx6;Erbb4F/Fn = 9, 7 female, 2 male) binding did not significantly differ by genotype. dHip CA1: dorsal hippocampus CA1; mHip CA3: middle hippocampus CA3; mHip CA1/2: middle hippocampus CA1/CA2; vHip CA3: ventral hippocampus CA3; dHip DG: dorsal hippocampus dentate gyrus; mHip DG: dentate gyrus.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Marín O. Interneuron dysfunction in psychiatric disorders. Nat Rev Neurosci. 2012;13(2):107–120. doi:10.1038/nrn3155. - DOI - PubMed
    1. Heckers S, Konradi C.. GABAergic mechanisms of hippocampal hyperactivity in schizophrenia. Schizophr Res. 2015;167(1):4–11. doi:10.1016/j.schres.2014.09.041. - DOI - PMC - PubMed
    1. Heckers S, Stone D, Walsh J, Shick J, Koul P, Benes FM.. Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. Arch Gen Psychiatry. 2002;59(6):521–529. doi:10.1001/archpsyc.59.6.521. - DOI - PubMed
    1. Benes FM, Kwok EW, Vincent SL, Todtenkopf MS.. A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives. Biol Psychiatry. 1998;44:88–97. doi:10.1016/S0006-3223(98)00138-3. - DOI - PubMed
    1. Benes FM, Khan Y, Vincent SL, Wickramasinghe R.. Differences in the subregional and cellular distribution of GABAA receptor binding in the hippocampal formation of schizophrenic brain. Synapse. 1996;22(4):338–349. doi:10.1002/(SICI)1098-2396(199604)22:4<338::AID-SYN5>3.0.CO;2-C. - DOI - PubMed

Publication types