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

Alena Savonenko, T. Melnikova, F. M. Laird, K. A. Stewart, D. L. Price, Philip Chun Wong

Research output: Contribution to journalArticle

Abstract

β-Site APP-cleaving enzyme 1 (BACE1) is required for the penultimate cleavage of the amyloid-β precursor protein (APP) leading to the generation of amyloid-β 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 signalingmayparticipate in the pathogenesis of schizophrenia and related psychiatric disorders.

Original languageEnglish (US)
Pages (from-to)5585-5590
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number14
DOIs
StatePublished - Apr 8 2008

Fingerprint

Neuregulin-1
Schizophrenia
Phenotype
Amyloid beta-Protein Precursor
Spine
Dizocilpine Maleate
Pyramidal Cells
Clozapine
Amyloid
Antipsychotic Agents
Psychiatry
Axons
Rodentia
Alzheimer Disease
Hypersensitivity
Peptides
Brain
Enzymes

Keywords

  • Clozapine
  • Dizocilpine
  • Neuregulin
  • Prepulse inhibition
  • Spine density

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. / Savonenko, Alena; Melnikova, T.; Laird, F. M.; Stewart, K. A.; Price, D. L.; Wong, Philip Chun.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 14, 08.04.2008, p. 5585-5590.

Research output: Contribution to journalArticle

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AB - β-Site APP-cleaving enzyme 1 (BACE1) is required for the penultimate cleavage of the amyloid-β precursor protein (APP) leading to the generation of amyloid-β 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 signalingmayparticipate in the pathogenesis of schizophrenia and related psychiatric disorders.

KW - Clozapine

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