Borna Virus Infected Neonatal Rats Activate ERK-CREB-BDNF Pathway Causing Anxiety And Autistic Phenotypes

Background: Borna disease virus(BDV)is a neurotropic,noncytopathic RNA viruse,belonging to the family Bornaviridae in the order Mononegavirales.Its primary property is persistently infects the central nervous system(CNS)of wide range of vertebrates species,causing neurological diseases and behavioral disorders.Over the past decade,substantial information indicated that BDV has great concern with psychiatric disorder in human,even though there still existed a controversial between human psychogenic disease and BDV.Mood disorder,such as anxiety,autism,schizophrenia,major depressive disorders,is common and life-threatening diseases.Mounting evidences indicates that the pathogenesis of mood disorder and BDV-induced illness in animal may be intimately pertinent.Up to now,BDV has been reported to be involved in complex etiopathogenesis,including the T-cell-mediated cytotoxicity,and microglial involved cytokine-mediated neurotoxicity,as well as disturbances in dopaminergic,GABAergic and glutamatergic system.Nevertheless,the detailed neuropathogenesis of BDV still remains largely unknown.Strain V,a reference strain,is horse-derived,rabbit-adapted.BDV Hu-H1,a human strain of BDV isolated from PBMCs of patients with major mood disorders by German scientists in 1996.In our previous research,based on the two strains shows that Hu-H1 not Strain V inhibited proliferation and promoted apoptosis in Human oligodendroglial cells(OL cells).The significantly different biological properties in vitro revealed the distinction between the two strains.Additionally,BDV Hu-H1 was used to infect human OL cells,resulting in the significant disturbance in Raf/MEK/ERK signaling pathway.Consistent with this,BDV CRP4 caused constitutive activation of ERK1/2 signaling in PC12 cells,impairing neuronal differentiation.Moreover,BDNF-induced phosphorylation of ERK 1/2 was repressed by BDV infection in neurons and accompanied with a normal synthesis of TrkB receptor.All aforementioned studies were experimented in vitro but lack of research in vivo.The Raf/MEK/ERK signaling cascade belonging to mitogen-activated protein kinase(MAPK)signaling pathway family has been relevant to a variety of processes of neuronal cell proliferation,differentiation,growth and apoptosis as well as in activation of many RNA viruses.In addition,ERK-CREB-BDNF pathway also participated in pathophysiology of MDD,Anxiety and Autistic Disorder.Based on which,herein we aim to validate the relationship between BDV and mood disorder.Objective: Herein,we focus on how the two different Borna viral strains(BDV Hu-H1 and BDV strain V)inducing neuronal changes affected by the ERK-CREB-BDNF pathway in vivo and in vitro simultaneously for further investigation on psychiatric diseases.Methods: In this study,we intracranially incubated Borna disease virus Hu-H1 and Strain V into left paracele of rats within 24 hours respectively.The identification of psychological-related phenotype was measured by sucrose preference test,open field test,elevated plus maze and forced swim test.Furthermore,the tipical ERK-CREB-BDNF signaling pathway was detected by Western Blot in vivo and in vitro.Results: Hu-H1-infected rats inoculated at postnatal day 1(P1)significantly decreased in locomotor activity and exploration behavior at OPT and EPM,which suggested Hu-H1 may cause anxiety-like symptoms,while Strain V-infected rats displayed autistic-like behavior via OPT,EPM and FST.Moreover,in identification of the ERK-CREB-BDNF pathway in two viruses-infected rats' hippocampus we found that p-44/42 MAPK was notably up-regulated(Strain V and Hu-H1-infected rats vs.control groups)and other molecular either increased or indicated a rising trend(p-MEK1/2,p-CREB,CREB,and BDNF).Unlike the changes in vivo,the expression of p-MSK1 was attenuated in primary hippocampal neurons when infected with two viruses respectively.Conclusion: Taken together,our results indicated that Borna disease virus Hu-H1 and Strain V infected neonatal rats resulted in behavioral abnormalities(anxiety-like or autistic-like behavior)which shared common molecular pathways(ERK-CREB-BDNF signaling cascade)with anxiety and autisim,providing a novel tool to investigate the underlying mechanisms of human psychiatric disorders.