Role Of Neuregulin 1-ErbB4 Signaling In Parvalbumin Interneurons In The Antidepressant Properties Of Ketamine

Objective:Recent clinical researches have indicated that ketamine, a general anesthetic, exerts rapid and robust antidepressant effects even in treatment-resistant patients, which makes it the important tool drug to study the pathogenesis and new treatment target point of depression, however, the underlying mechanisms are not totally understood. Meanwhile, some studies have demonstrated that neuregulin 1 (NRG1) is a bipolar disorder susceptibility gene and a biomarker of major depressive disorder, which regulates pyramidal neuron activity via ErbB4 in parvalbumin (PV) interneurons. Moreover, NRG1-ErbB4 signaling is reported to play a key role in the modulation of synaptic plasticity through regulating the neurotransmission. Given this, we hypothesize that NRG1-ErbB4 signaling in PV interneurons may play an important role in ketamine’s antidepressant effects. This study aims to observe the changed levels of NRG1, ErbB4, p-ErbB4, PV, glutamate decarboxylase 67 (GAD67), gamma-aminobutyric acid (GABA) and glutamate (Glu) in ketamine’s antidepressant actions, and to investigate the effects of NRG1-ErbB4 signaling in PV interneurons in the antidepressant properties of ketamine.Methods:Seven days after the intracerebroventricular cannulation, a total of 32 male Wistar rats were equally randomized into 4 groups (n=8):control group, depression group (DMSO+sal group), ketamine group (DMSO+ket group), and ketamine+NRG1-β1 group (NRG1-β1+ket group). Rats in depression group, ketamine group, and ketamine+NRG1-β1 group received forced swimming test (FST) to establish an acute rat model of depression. Twenty-four hours later, rats in 4 groups were intracerebroventricularly infused with DMSO, DMSO, DMSO and NRG1-β1. Thirty minutes later, rats in 4 groups were injected with saline, saline, ketamine, and ketamine, respectively. Thirty minutes later, the locomotor activities and the scores of stereotyped behavior in open field test (OFT), the immobility time in FST and latency to feed in novelty-suppressed feeding test (NSFT) were observed and recorded to detect the behavior changes. Double lable immunofluorescent staining was employed to evaluate colocalization of PV and GAD67 and PV and ErbB4 in the hippocampus and prefrontal cortex (PFC) of control rats. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of NRG 1, Glu and GAB A and Western Blot was adopted to assess the levels of p-ErbB4, ErbB4, PV and GAD67 of the rat hippocampus and PFC immediately after the behavior test.Results:GAD67 was primarily expressed in the PV-immunoreactive interneurons and the average coexpression of PV and GAD67 in GAD67-positive interneurons was 48.65±9.42% across the hippocampus and 46.73±8.83% across the PFC. The average coexpression of PV and ErbB4 in PV-positive interneurons was 81.79±10.27% across the hippocampus and 80.03±10.13% across the PFC and in ErbB4-positive neurons was 64.83±9.53% across the hippocampus and 65.76±10.73% across the PFC in control rats. Compared with the control group, exposure to FST increased the immobility time in FST (P<0.05) and latency to feed in NSFT (P< 0.05), upregulated the expression of p-ErbB4, PV, GAD67 and the levels of NRG1 and GABA, and downregulated Glu levels in the rat hippocampus and PFC. Compared with the depressed group, ketamine administration reduced the immobility time and latency to feed of rats receiving the FST, downregulated the expression of p-ErbB4, PV, GAD67 and the levels of NRG 1 and GABA, and upregulated Glu levels in the rat hippocampus and PFC. Compared with the ketamine group, preadministration with NRG1-β1 before ketamine administration abolished both ketamine’s antidepressant effects (P< 0.05) and ketamine-induced changed levels of p-ErbB4, PV, GAD67, NRG1, GABA and Glu (P< 0.05). However, FST and drug administration had no significant effects on the locomotor activities and the stereotypic movements of rats (P>0.05).Conclusions:The downregulation of NRG1-ErbB4 signaling in PV interneurons in the rat brain may have important significance in ketamine’s antidepressant properties, which may be associated with the disinhibition of Glu neurotransmission and the increase of the activation of pyramidal cells.