Journal Article

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

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

2008

Overview

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 signaling may participate in the pathogenesis of schizophrenia and related psychiatric disorders.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Alzheimer disease / Amyloid Precursor Protein Secretases - deficiency / Amyloid Precursor Protein Secretases - physiology / Animal models / Animals / antipsychotics / Aspartic Acid Endopeptidases - deficiency / Aspartic Acid Endopeptidases - physiology / axons / Behavior, Animal / Behavioral neuroscience / Biological Sciences / Dendrites / Hippocampus - pathology / Hyperactivity / hypersensitivity / Mice / Mice, Knockout / myelination / Neuregulin-1 - metabolism / Neuregulins / Neurons / pathogenesis / peptides / phenotype / Phenotypes / proteolysis / Receptor, Epidermal Growth Factor - metabolism / Receptor, ErbB-4 / Receptors / Schizophrenia / Schizophrenia - etiology / Signal Transduction