title: Olanzapine Prevents the PCP-induced Reduction in the Neurite Outgrowth of Prefrontal Cortical Neurons via NRG1.
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.
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, 2522, NSW, Australia.|Illawarra Health and Medical Research Institute, Wollongong, 2522, NSW, Australia.
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, 2522, NSW, Australia.|Illawarra Health and Medical Research Institute, Wollongong, 2522, NSW, Australia.|Schizophrenia Research Institute, 384 Victoria Street, Darlinghurst, 2010, NSW, Australia.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, 2522, NSW, Australia.|Illawarra Health and Medical Research Institute, Wollongong, 2522, NSW, Australia.|Schizophrenia Research Institute, 384 Victoria Street, Darlinghurst, 2010, NSW, Australia.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology*; D023902:Chromosome Pairing / Q000187:drug effects; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020890:Neuregulin-1 / Q000378:metabolism*; D000071446:Neuronal Outgrowth / Q000187:drug effects*; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D000077152:Olanzapine; D010622:Phencyclidine / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate; D016708:Synaptophysin; D001569:Benzodiazepines; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D010622:Phencyclidine; D000077152:Olanzapine