The Role Of PGC-1? Involved In Synaptic Plasticity In The Observation Of A Gene×Environment Interaction In Schizophrenia

Schizophrenia(SCZ)is a neurodevelopmental disorder,which is involved in abnormality of brain anatomy,gene deletion or mutation.A redox dysregulation due to genetic and/or environmental factors might contribute to SCZ pathophysiology.Peroxisome proliferator activated receptor PPAR? coactivator-?(PGC-1?)is concentrated in GABAergic neurons during early postnatal development of the rodent brain in the central nervous system,and was identified as one of the top candidate genes of SCZ.However,the relevance of PGC-1? gene deltetion and the occurrence of SCZ and its potential mechanisms are still not fully,systematically and deeply understood.Objectives(1)We aim to answer the question whether PGC-1? defict can mediate the occurrence of SCZ.(2)We aimed to investigate whether PGC-1? defict can mediate the erroneous regulation of the critical period(CP)during the neurodevelopment in SCZ.(3)We further want to certificate whether PGC-1? can regulate synaptic plasticity via gene × environment interaction.Methods(1)We first generated PGC-1? conditional knockout mice in GABAergic neurons through Cre/Loxp gene recombination technology.New object recognition,prepulse inhibition and morris water maze experiments were explored to evaluate the relevance of PGC-1? deficit and the occurance of SCZ.(2)The maturation of parvalbumin interneurons(PVIs)and their perineuronal nets(PNNs)was detected to investigate whether PGC-1? conditional knockout can mediate the erroneous regulation of the CP during the neurodevelopment in SCZ.(3)PGC-1? deficient mice were utilized to mimic gene susceptibility of SCZ and an additional oxidative stress was induced by GBR injection.We detected the cortical neurons damage and the expression levels of parvalbumin(PV)and PNNs in PGC-1? knockout mice at different stages of neurodevelopment(juvenile/adulthood).We aimed to evaluate that whether PGC-1? can regulate synaptic plasticity via gene × environment interaction at different stages of neurodevelopment.(4)The chABC enzyme was locally infused into retrosplenial cortex(RC)to degrade PNNs and an additional oxidative stress was induced by GBR injection.Then we detected the cortical neurons damage and the expression levels of PV in PGC-1? knockout mice at early adult age.We aimed to evaluate that whether PGC-1? can regulate synaptic plasticity via gene × environment interaction at reopening CP.Results(1)Mice lacking the PGC-1? gene exhibited deficits in short-term habituation,hyperactivity,reduced prepulse inhibition and exaggerated startle reactivity but normal associative spatial reference memory.(2)These behavioral dysfunctions were associated with decreased PV expression in the cortex(including somatosensory and motor cortex)as well as in the hippocampus,especially in its CA1 and CA3 regions.(3)Adult(P90)PGC-1? KO mice showed increased DNA damage marker and delayed maturation of PVIs in their RC.(4)PGC-1? gene deletion and chronic oxidative stress had a synergic action on DNA damage and delayed maturation of PVIs in the RC of P20 PGC-1? KO mice.(5)PGC-1? gene deletion and chronic oxidative stress had no synergic action on DNA damage and PVIs maturation in the RC of P90 PGC-1? KO mice.(6)The synergic action of gene × environment is available in ChABC-infused mice in the RC of 90 PGC-1? KO mice.Conclusions(1)PGC-1? difict mediated the occurance of SCZ;(2)PGC-1? difict delayed the maturation of PVIs and PNNs,which mediating the abnormality of CP during the neurodevelopment in SCZ;(3)PGC-1? regulated neuroplasticity via gene×environment interaction.Above all,PGC-1? involved in synaptic plasticity of PVIs in the observation of a gene-environment interaction in SCZ.