Erbb4 Deletion from Medium Spiny Neurons of the Nucleus Accumbens Core Induces Schizophrenia-Like Behaviors via Elevated GABA A Receptor α1 Subunit Expression

• Published in: The Journal of neuroscience 2017-08, Vol.37 (31), p.7450-7464
• Main Authors: Geng, Hong-Yan, Zhang, Jing, Yang, Jian-Ming, Li, Yue, Wang, Ning, Ye, Mao, Chen, Xiao-Juan, Lian, Hong, Li, Xiao-Ming
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal; Gene Expression Regulation; Male; Mental Disorders - etiology; Mental Disorders - physiopathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Neural Inhibition; Neurons - metabolism; Nucleus Accumbens - physiopathology; Receptor, ErbB-4 - genetics; Receptor, ErbB-4 - metabolism; Receptors, GABA-A - metabolism; Schizophrenia - physiopathology; Tissue Distribution; Up-Regulation
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3948-16.2017

Medium spiny neurons (MSNs), the major GABAergic projection neurons in the striatum, are implicated in many neuropsychiatric diseases such as schizophrenia, but the underlying mechanisms remain unclear. We found that a deficiency in , a schizophrenia risk gene, in MSNs of the nucleus accumbens (NAc) core, but not the dorsomedial striatum, markedly induced schizophrenia-like behaviors such as hyperactivity, abnormal marble-burying behavior, damaged social novelty recognition, and impaired sensorimotor gating function in male mice. Using immunohistochemistry, Western blot, RNA interference, electrophysiology, and behavior test studies, we found that these phenomena were mediated by increased GABA receptor α1 subunit (GABA R α1) expression, which enhanced inhibitory synaptic transmission on MSNs. These results suggest that in MSNs of the NAc core may contribute to the pathogenesis of schizophrenia by regulating GABAergic transmission and raise the possibility that GABA R α1 may therefore serve as a new therapeutic target for schizophrenia. Although ErbB4 is highly expressed in striatal medium spiny neurons (MSNs), its role in this type of neuron has not been reported previously. The present study demonstrates that deletion in nucleus accumbens (NAc) core MSNs can induce schizophrenia-like behaviors via elevated GABA receptor α1 subunit (GABA R α1) expression. To our knowledge, this is the first evidence that ErbB4 signaling in the MSNs is involved in the pathology of schizophrenia. Furthermore, restoration of GABA R α1 in the NAc core, but not the dorsal medium striatum, alleviated the abnormal behaviors. Here, we highlight the role of the NAc core in the pathogenesis of schizophrenia and suggest that GABA R α1 may be a potential pharmacological target for its treatment.