Abstract
Dysfunction of the noradrenergic (NE) neurons is implicated in the pathogenesis of bipolar disorder (BPD). ErbB4 is highly expressed in NE neurons, and its genetic variation has been linked to BPD; however, how ErbB4 regulates NE neuronal function and contributes to BPD pathogenesis is unclear. Here we find that conditional deletion of ErbB4 in locus coeruleus (LC) NE neurons increases neuronal spontaneous firing through NMDA receptor hyperfunction, and elevates catecholamines in the cerebrospinal fluid (CSF). Furthermore, Erbb4-deficient mice present mania-like behaviors, including hyperactivity, reduced anxiety and depression, and increased sucrose preference. These behaviors are completely rescued by the anti-manic drug lithium or antagonists of catecholaminergic receptors. Our study demonstrates the critical role of ErbB4 signaling in regulating LC-NE neuronal function, reinforcing the view that dysfunction of the NE system may contribute to the pathogenesis of mania-associated disorder.
Highlights
Bipolar disorder (BPD), diagnosed on the basis of manic episodes with or without depression, is a severely debilitating psychiatric disorder (Holden, 2008)
We examined Cre expression in the locus coeruleus (LC), ventral tegmental nucleus (VTA), and substantia nigra pars compacta (SNC) of Ai9;Th-Cre mice at postnatal day (P) 50 because tyrosine hydroxylase (TH), the key enzyme for the synthesis of norepinephrine and dopamine, is mainly expressed in these three
We show that disruption of ErbB4 in LC-NE neurons causes NMDA receptor-mediated hyperactive spontaneous firing of LC-NE neurons and elevates cerebrospinal fluid (CSF) norepinephrine and dopamine concentrations, which induce mania-like behaviors that could be rescued by lithium or noradrenergic and dopaminergic receptor antagonists
Summary
Bipolar disorder (BPD), diagnosed on the basis of manic episodes with or without depression, is a severely debilitating psychiatric disorder (Holden, 2008). The concentrations of norepinephrine and its metabolites are significantly upregulated in the cerebrospinal fluid (CSF) of BPD patients during the manic state (Kurita, 2016; Manji et al, 2003; Post et al, 1973; Post et al, 1978). Norepinephrine is downregulated in patients with depressive disorder (Maas et al, 1971; Moret and Briley, 2011; Wiste et al, 2008) and associated with mood transition in BPD patients (Kurita, 2016; Salvadore et al, 2010). How the NE system is involved in the pathology of BPD remains uncertain
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