Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice.
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.
Savonenko
A V
AV
Departments of Pathology, Neurology, and Neuroscience, Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Baltimore, MD 21205, USA.
Melnikova
T
T
Laird
F M
FM
Stewart
K-A
KA
Price
D L
DL
Wong
P C
PC
D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency / Q000502:physiology*; D001522:Behavior, Animal; D066246:ErbB Receptors / Q000378:metabolism*; D006624:Hippocampus / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020890:Neuregulin-1 / Q000378:metabolism*; D066247:Receptor, ErbB-4; D012559:Schizophrenia / Q000209:etiology*; D015398:Signal Transduction
D020890:Neuregulin-1; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse