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

Abstract

␤-Site APP-cleaving enzyme 1 (BACE1) is required for the penultimate cleavage of the amyloid-␤ precursor protein (APP) leading to the generation of amyloid-␤ 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.clozapine ͉ dizocilpine ͉ neuregulin ͉ prepulse inhibition ͉ spine density B ACE1 (␤-site APP-cleaving enzyme 1), is the rate-limiting enzyme that makes the initial cleavage of the amyloid-␤ (A␤) precursor protein (APP) and, in concert with ␥-secretase, gives rise to the plaque-forming ␤-amyloid peptides in Alzheimer's disease (AD) (1). Deletion of BACE1 prevents the formation of A␤ in vitro and in vivo and the cognitive abnormalities in mouse models of A␤ amyloidosis. These findings strongly support BACE1 as an attractive therapeutic target for AD (1-3). In addition to APP, a number of other putative substrates for BACE1 have been identified, suggesting that BACE1 has multiple physiological functions (2). For example, recent studies indicate that BACE1 participates in the proteolytic processing of neuregulin 1 (NRG1) (4, 5), a ligand for members of the ErbB family of receptor-tyrosine kinases. This signaling pathway have numerous roles in CNS development and functions, including synapse formation, plasticity, neuronal migration, myelination of central and peripheral axons, and the regulation of neurotransmitter expression and function (6, 7). In addition to these physiological functions, NRG1 is one of the first genes that has been linked to an increased risk of schizophrenia (8). The disease-associated single-nucleotide polymor...

Antipsychotic treatment and neuregulin 1–ErbB4 signalling in schizophrenia

“…These differences are partly due to the fact that patients' risk genotypes have only some subtle variations, while transgenic mice have a pronounced gene alteration (Banerjee et al, 2010), or partly due to the duration of the modification of NRG1 signalling (Savonenko et al, 2008). Furthermore, dysregulated NRG1-ErbB4 signalling in schizophrenia might interact with other signalling pathways such as glutamatergic, GABAergic and dopaminergic pathways (Banerjee et al, 2010;Buonanno, 2010).…”

“…The effects of clozapine on suppressing hyperactivity have also been observed in open-field and running wheel tests in the NRG1 Ig-like domain mutant mice (Rimer et al, 2005), and in novelty-induced hyperactivity in BACE1-knockout mice. Although the deficits in PPI have been observed in NRG1 EGF-and BACE1-knockout mice, the effects of clozapine on improving PPI have been observed in BACE1-knockout mice (Savonenko et al, 2008), but not in NRG1 EGF-mutant mice (Stefansson et al, 2002). Furthermore, deficits of PPI could be reversed to normal level both haloperidol or clozapine in Aph1B/C-γ-secretase-disturbed mice (Dejaegere et al, 2008).…”

“…In the last decade, animal studies have shown that animals with abnormal NRG1-ErbB4 functions display schizophrenia-like behavioural abnormalities, including hyperactivities in the novel open-field test and the alternating-Y maze (Barros et al, 2009;Duffy et al, 2008;Gerlai et al, 2000;O'Tuathaigh et al, 2007;Rimer et al, 2005;Stefansson et al, 2002;van den Buuse et al, 2009), deficits in prepulse inhibition (PPI) level (Barros et al, 2009;Dejaegere et al, 2008;Hong et al, 2008;Savonenko et al, 2008;Stefansson et al, 2002;van den Buuse et al, 2009), and lateral inhibition (Rimer et al, 2005), as well as impaired social activities (O'Tuathaigh et al, 2007). These reports provided evidence supporting the potential roles of mutations in NRG1 and ErbB4 genes as risk factors for schizophrenia.…”

“…NRG1-induced stimulation of the ErbB4 receptor plays critical roles in the neuronal functions that are closely related to the development of schizophrenia, mainly neuronal specification, neuronal migration, neuron-glial signalling, synapse formation, synaptic transmission, and plasticity of the CNS (for review: see Harrison and Law, 2006). Several studies found that animals with impaired NRG1-ErbB4 signalling displayed schizophrenia-like behavioural abnormalities (Barros et al, 2009;Dejaegere et al, 2008;Rimer et al, 2005;Savonenko et al, 2008;Stefansson et al, 2002).…”

β-Site Amyloid Precursor Protein (APP)-cleaving Enzyme 1 (BACE1)-deficient Mice Exhibit a Close Homolog of L1 (CHL1) Loss-of-function Phenotype Involving Axon Guidance Defects

“…Initial reports indicated that BACE1 Ϫ/Ϫ mice were viable, fertile, and devoid of abnormalities. However, upon closer examination, BACE1 Ϫ/Ϫ mice were found to have several subtle phenotypes that involved memory deficits (16 -18), hypomyelination (19,20), reduced survival and growth retardation (21), irregularities in neuronal excitability and electrophysiology (17,21,22), seizure (22,23), reduced dendritic spine density (24), schizophrenia endophenotypes (24), and axon guidance defects (1,25). Although these BACE1 null abnormalities are relatively mild, they are complex neurological phenotypes that raise a concern that BACE1 inhibitors may not be completely free of mechanism-based side effects.…”