Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1 -null mice

Savonenko, A. V.; Melnikova, T.; Laird, F. M.; Stewart, K.-A.; Price, D. L.; Wong, P. C.

doi:10.1073/pnas.0710373105

Cited by 291Schizophrenia research and treatmentAlzheimer's disease research and treatmentsNeuroscience and Neuropharmacology Research

Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1 -null mice

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Savonenko, A. V., Melnikova, T., Laird, F. M., Stewart, K.-A., Price, D. L., Wong, P. C.·2008·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0710373105PMC PMC2291091

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Abstract

beta-Site APP-cleaving enzyme 1 (BACE1) is required for the penultimate cleavage of the amyloid-beta precursor protein (APP) leading to the generation of amyloid-beta peptides that is central to the pathogenesis of Alzheimer's disease. In addition to its role in endoproteolysis of APP, BACE1 participates in the proteolytic processing of neuregulin 1 (NRG1) and influences the myelination of central and peripheral axons. Although NRG1 has been genetically linked to schizophrenia and NRG1(+/-) mice exhibit a number of schizophrenia-like behavioral traits, it is not known whether altered BACE1-dependent NRG1 signaling can cause similar behavioral abnormalities. To test this hypothesis, we analyze the behaviors considered to be rodent analogs of clinical features of schizophrenia in BACE1(-/-) mice with impaired processing of NRG1. We demonstrate that BACE1(-/-) mice exhibit deficits in prepulse inhibition, novelty-induced hyperactivity, hypersensitivity to a glutamatergic psychostimulant (MK-801), cognitive impairments, and deficits in social recognition. Importantly, some of these manifestations were responsive to treatment with clozapine, an atypical antipsychotic drug. Moreover, although the total amount of ErbB4, a receptor for NRG1 was not changed, binding of ErbB4 with postsynaptic density protein 95 (PSD95) was significantly reduced in the brains of BACE1(-/-) mice. Consistent with the role of ErbB4 in spine morphology and synaptic function, BACE1(-/-) mice displayed reduced spine density in hippocampal pyramidal neurons. Collectively, our findings suggest that alterations in BACE1-dependent NRG1/ErbB4 signaling may participate in the pathogenesis of schizophrenia and related psychiatric disorders.

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Self-citation

Authors: Savonenko, A. V., Melnikova, T., Laird, F. M., Stewart, K.-A., Price, D. L., & Wong, P. C.
Affiliations: Johns Hopkins University (US)
The University of Texas Southwestern Medical Center (US)
Corresponding author: Wong, P. C.
ORCID: Savonenko, A. V.
Wong, P. C.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2008-04-08
Volume: 105
Issue: 14
Pages: 5585-5590
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0710373105
PMC: PMC2291091
OpenAlex: W2063978545
Cited by: 290
References: 39
Citations by year: 2026: 8 · 2025: 4 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 9 · 2020: 6 · 2019: 12 · 2018: 10 · 2017: 16 · 2016: 27 · 2015: 24 · 2014: 23 · 2013: 20 · 2012: 24
FWCI: 21.26
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Alzheimer's Association
Bristol-Myers Squibb Foundation
Bristol-Myers Squibb
National Institutes of Health
National Institute on Aging (P50AG005146, P50AG05146)
National Institute of Neurological Disorders and Stroke (R01 NS41438, P01NS047308, R01NS041438)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: BACE1, neuregulin-1, ERBB4 signaling, schizophrenia, prepulse inhibition, cognitive impairment, social recognition, clozapine, PSD-95, dendritic spine density, hippocampal pyramidal neurons, synaptic function
MeSH terms: Animals, Behavior, Animal, Hippocampus, Schizophrenia, Signal Transduction, Aspartic Acid Endopeptidases, Mice, Knockout, Neuregulin-1, Mice, Amyloid Precursor Protein Secretases, ErbB Receptors, Receptor, ErbB-4

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Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1 -null mice

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