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β-Site APP-cleaving Enzyme 1 (BACE1) is an endopeptidase responsible for proteolytic processing of several proteins including amyloid-precursor protein (APP) and neuregulin 1 (NRG1), a promising schizophrenia candidate gene (Petryshen et al. 2005; Stefansson et al. 2003a,b; Walss-Bass et al. 2006; Williams et al. 2003; Yang et al. 2003; Zhao et al. 2004). BACE1 cleaves NRG1 at the extracellular site, liberating the NRG1 N-terminal domain for interaction with ErbB tyrosine-kinase receptors and activation of downstream signaling events. BACE1 knockout mice (BACE1−/−) show an increase in full-length NRG1, reflecting lack of protein cleavage. These animals exhibit behaviors similar to mice with impaired NRG1 function, including impaired prepulse inhibition and novelty-induced hyperactivity (Luo et al. 2014; Savonenko et al. 2008; Willem et al. 2009), that are considered rodent analogs of schizophrenia behavior in humans. BACE1−/− furthermore exhibit morphological characteristics resembling those found in schizophrenia, including hypomyelination, decreased CA1 spine density and neuronal number, all of which are potentially consequences of altered NRG1-ErbB4 signaling (Hu et al. 2006). Importantly, genetic variants within BACE1 have been shown to correlate significantly with variants within other genes in the NRG1-ErbB4 signaling pathway in schizophrenia families (Hatzimanolis et al. 2013). At the cellular level, enhanced striatal dopamine (DA) release from the terminals of midbrain DA neurons may underlie the positive symptoms of schizophrenia, i.e. hallucinations and delusions (Howes et al. 2012; Lyon et al. 2011). Previous studies have observed functional impairment of the prefrontal striatonigral circuit characterized by task-evoked hyperactivity of the substantia nigra in schizophrenia patients (Yoon et al. 2013). Terminal DA release from midbrain DA neurons is inhibited by D2 DA autoreceptors that are located on their cell bodies, dendrites and axon terminals. In the midbrain, somatodendritic DA release from neighboring DA neurons activates D2 autoreceptors and induces a potassium conductance that inhibits firing frequency (Lacey et al. 1987; Pucak & Grace 1994). Synaptic depression of D2 autoreceptor function can attenuate firing inhibition and thus increases excitability (Beckstead & Williams 2007), which could contribute to midbrain hyperdopaminergia in schizophrenia. Local perfusion with NRG1 stimulates DA release in the hippocampus (Kwon et al. 2008), and intra-striatal injection of NRG1 evokes an almost immediate overflow of striatal DA (Yurek et al. 2004). However, little is known about how disruption of BACE1-mediated cleavage of NRG1 affects midbrain DA signaling and related behaviors. In light of the previous studies showing NRG1 stimulation of DA release, we hypothesized that because of impaired NRG1 cleavage, mice with a BACE1 deletion would exhibit a diminished behavioral response to amphetamine, an indirect DA agonist, with concurrent alterations in DA neuron excitability. In agreement with our hypothesis, we show that BACE1−/− mice exhibit a decrease in sensitivity to the locomotor activation produced by amphetamine. Striatal levels of DA and DA metabolites were unaltered in these mice. Substantia nigra DA neurons from BACE1−/− exhibited enhanced amphetamine-induced D2 autoreceptor-mediated currents and basal firing rate. The increased autoreceptor-mediated inhibition provides a plausible mechanism to explain the decreased sensitivity to amphetamine-induced locomotion in BACE1−/− mice. |
