ErbB4 Dclction In Catecholaminergic Neurons Induces Manic-like Behavior

ErbB4 is a tyrosine kinase receptor with single transmember structure. It is also a member of the epidermal growth factor receptor family. ErbB4 have crucial roles in neural development and functions, ranging from proliferation, differentiation, migration, axon growth and guidance to synapse formation and plasticity. As an important susceptibility factor for schizophrenia, ErbB4 attracts a lot of attentions in recent years. Previous studies show that ErbB4 mRNA is also localized in catecholaminergic (CA) neurons, primarily in norepinephrine (NE) and dopamine (DA) neurons in the locus coeruleus (LC), ventral tegmental area (VTA) and substantia nigra pars compacta (SNC). In central nervous system, both NE and DA are important neuromodulators and menbers of CA system. Previous studies show that NE and DA participate in many important functions including locomotion, decision making, cognition, reward, stress and arousal, and is also play an important roles in mood disorders like mania, depression and bipolar disoder. While the role of ErbB4 in CA neurons is unclear.Here, with the application of technologies including molecular genetics, biochemistry, electrophysiology and microdialysis, we show the roles of ErbB4 in CA neurons. ErbB4 is specific deleted in CA neurons by crossing TH-cre mice with mice carrying a loxP-flanked Erbb4 gene (TH-cre; Erbb4-/- mice, cKO). We demonstrate that:First, ErbB4 was primarily deleted in LC-NE neurons in cKO mice. Second, ErbB4 deletion leaded to manic-like behaviors, including hyperactivity, decreased anxiety and depression and increased sucrose preference, which could be relieved by long-term lithium treatment. In addtion, cKO mice showed cognitive deficit. Third, the concentrations of NE and DA were increased in the cerebrospinal fluid (CSF) of cKO mice and both NE and DA contributed to the manic-like behaviors. Fourth, ErbB4 deletion had no significant effect on the morphology of LC-NE neurons, but the spontaneous firing of NE neurons and the phosphorylation of tyrosine hydroxylase (TH) were significantly increased. The protein level of dopamine beta-hydroxylase (DBH), norepinephrine transporter (NET), and catechol-o-methyltransferase (COMT), which is a key enzyme that degrades NE, were not significantly changed. Fifth, long-term lithium treatment significantly decreased the spontaneous firing of NE neurons and the TH phosphorylation.In a word, ErbB4 deletion in CA neurons, primarily in NE neurons leads to manic-like behaviors, which can be rescued by long-term lithium treatment. In addtion, cKO mice show cognitive defict. The concentrations of NE and DA are increased in CSF of cKO mice and both NE and DA contribute to the manic-like behaviors. Further study show that ErbB4 deletion has no significant effect on the morphology of LC-NE neurons, but the spontaneous firing of NE neurons and TH phosphorylation are significantly increased, which also can be rescued by long-term lithium treatment. Our data suggest that ErbB4 signaling in CA neurons might participate in the pathogenesis of mania and we indicate a new perspective for mania treatment.