Olanzapine Prevents the PCP-induced Reduction in the Neurite Outgrowth of Prefrontal Cortical Neurons via NRG1.

Qingsheng Zhang,Yinghua Yu,Xu-Feng Huang

doi:10.1038/srep19581

Abstract

Accumulating evidence suggests that reducing neurite outgrowth and synaptic plasticity plays a critical role in the pathology of cognitive deficits in schizophrenia. The N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) can induce symptoms of schizophrenia as well as reduce dendritic spine density and neurite growth. The antipsychotic drug olanzapine may improve these deficits. This study aimed to investigate: (1) if olanzapine prevents PCP-induced suppression of neurite outgrowth and synaptic protein expression; (2) if olanzapine affects the Akt-GSK3 signaling pathway; and (3) the role of neuregulin 1 (NRG1) in this process. Immunofluorescence revealed that PCP treatment for 24 hours reduces both neurite length (28.5%) and the number of neurite branches (35.6%) in primary prefrontal cortical neuron cultures. PCP reduced protein and mRNA expressions of synaptophysin (24.9% and 23.2%, respectively) and PSD95 (31.5% and 21.4%, respectively), and the protein expression of p-Akt (26.7%) and p-GSK3β (35.2%). Olanzapine co-treatment prevented these PCP-induced effects in normal neurons but not in neurons from NRG1-knockout mice. These results indicate that NRG1 mediates the preventive effects of olanzapine on the PCP-induced impairment of neurite outgrowth and synaptic protein expression. This study provides potential targets for interventions on improving the efficacy of olanzapine on preventing cognitive deficits in schizophrenia.

Highlights

Olanzapine is a second-generation antipsychotic drug that has been reported to have some improvement effects on neurocognitive dysfunction in schizophrenia patients[15,16,17]
Western blotting revealed that the protein expression of synaptophysin and PSD95 were both downregulated by PCP treatment for 24.9% (p < 0.05) and 31.5% (p < 0.01), respectively (Fig. 1d–f)
To determine whether the Akt-GSK signaling cascade is affected by PCP in vitro, we examined the mRNA expressions of TrkB and GSK3β as well as the protein expressions of Akt, phosphorylated Akt (p-Akt), GSK3β, and p-GSK3β in primary PFC cultures under PCP treatment

Summary

Introduction

Olanzapine is a second-generation antipsychotic drug that has been reported to have some improvement effects on neurocognitive dysfunction in schizophrenia patients[15,16,17]. The preventative effects of olanzapine on PCP-induced deficits in synaptic plasticity, pre-pulse inhibition, and cortical NMDAR expressions have been reported in rodents[19,20], suggesting a potential role of olanzapine in attenuating the cognitive dysfunctions in rodents, the efficacies of this antipsychotic www.nature.com/scientificreports/. It has been reported that NMDAR expression was reduced in NRG1 (∆TM)+ /− mice, and the phosphorylation of NR2B on Tyr1472, which is key to NMDAR’s channel property, was suppressed in NRG1 (∆TM)+ /− mice These suggest that NRG1-ErbB4 may act downstream of NMDAR stimulation[23]. We present evidence that olanzapine attenuates PCP’s inhibition effect on neurite outgrowth and synaptic plasticity, possibly through improving the PCP-induced downregulation of the NRG1 signaling pathway, and activating the downstream Akt-GSK cascade

Objectives

Results

Conclusion