| Schizophrenia is a serious mental illness whose pathogenesis is unknown.Susceptibility genes and high-risk environmental exposures may contribute to the development of schizophrenia.Susceptibility genes have always been core concerns in the etiology of schizophrenia.Disrupted in schizophrenia 1(DISC1)gene is one of the most important susceptibility genes of schizophrenia,and the animal models with DISC1 gene mutation have been successfully constructed.Environmental factors are closely related to schizophrenia.Our previous study found that multiple environmental insults(Hits)contributed more to construction of schizophrenia animal than single environment insult.Environmental factors include not only the external environment,but also the internal environment.Immune homeostasis is an important part of homeostasis.Many studies have found that immune dysregulation is associated with schizophrenia.Macrophage migration inhibitory factor(MIF)is an important immune factor,which regulates the secretion and release of a variety of cytokines.Our previous clinical study found that plasma MIF level significantly increased in patients with schizophrenia than that in healthy subjects.What’ more,the high expression of MIF gene is associated with negative symptoms of schizophrenia patients.The results suggested that MIF may play a role in the development of schizophrenia,but the mechanism is not clear.Thus,in this study,we will investigate the role of MIF,as an internal environment factor,in the pathogenesis of schizophrenia.Concerning the ratio of genic and environmental contribution to the development of schizophrenia,there are several hypotheses:(1)gene determination: schizophrenia is determined by genes.(2)Genes or environment: some schizophrenia genetically determined,some are determined by the environment.(3)gene-environment interaction: genes and environment are both necessary for schizophrenia.There are two hypotheses about the interaction between gene and environment:(1)gene or environment plays an important role in the development of schizophrenia separately;(2)specific gene controls the individual’s susceptibility to environmental factors.Schizophrenia is a polygenic inheritance disease,and a variety of environmental factors may be involved in the occurrence of disease.Therefore,in order to study the importance of gene and environment in the development of schizophrenia,we should consider the combination of many factors,including gene-environment or gene-gene interaction.Animal model is an important tool for exploration of the etiology of schizophrenia.Therefore,in this study,we not only study the role of MIF in the development of schizophrenia,but also use different interaction patterns of genes and environment to construct schizophrenia animal model.We aim to construct an animal model with stable structure and surface validity,which can be used to study the etiology of schizophrenia and provide an excellent tool for screening drugs.This paper includes the following parts:Part one: The role of MIF in the etiology of schizophreniaIn order to explore the role of MIF in the development of schizophrenia,firstly,we constructed induced a schizophrenia model by MK-801 and then observed the behavior phenotype and brain MIF expression.Secondly,we constructed a mouse model with cerebral MIF injection to observe their behaviors.Electrophysiological experiments were used to observe the effects of MIF on neuronal function.Thirdly,MIF knockout and MIF inhibitor injection were used to mimic MIF deficits respectively,and then observe the behavioral phenotype.We found that MK-801 induced mice showed high activity and social withdrawal,as well as an increase of MIF protein expression in the brain.Mice with MIF injection showed low social activity and impaired PPI.In addition,we found that MIF gene knockout(MIF-/-)mice showed schizophrenia-like behavior in adulthood,such as social withdrawal,cognitive impairment,reduced PPI and anxiety-like behavior.Mice with neonatal injection of MIF inhibitor ISO-1 showed impaired PPI,and mice with adolescent injection of ISO-1 showed anxiety-like behavior.In summary,our previous clinical studies have demonstrated that MIF gene expression was highly associated with the negative symptoms of schizophrenia,while MK-801 or MIF injection can both induce schizophrenia-like negative symptoms,suggesting that MIF expression is associated with negative symptoms of schizophrenia.In addition,MIF knockout mice showed significant schizophrenia-like behavior,suggesting that MIF gene deficiency may be a novel genetic variation that is associated with schizophrenia.Part two: A schizophrenia mouse model constructed by interaction between MIF gene knockout and multiple environmental insultsIn order to construct a more stable and effective schizophrenia model that can be used to verify the role of interaction between gene and environment in development of schizophrenia,we combined MIF gene knockout mouse with multiple environment insults to construct a mouse model,and then assess behavioral phenotype of mouse model through open field,social interaction,elevated plus maze,forced swimming and so on.Although MIF gene knockout combined with multiple environmental insults showed no significant schizophrenia-like behavioral phenotype,the results suggested that MIF can be regulated by the impact of the external environment.In a word,the results verified the interaction between environmental insults and gene expression.Part three: A schizophrenia mouse model constructed by interaction between DISC1 gene mutation and multiple environmental insultsIn order to construct a more stable and effective schizophrenia model that can be used to verify the role of interaction between gene and environment in development of schizophrenia,we combined DISC1 gene mutation with multiple environmental insults to construct a mouse model,and then assess behavioral phenotype of mouse model through open field,social interaction,elevated plus maze,forced swimming and so on.At last,we observed the therapeutic effect of olanzapine on schizophrenia like-behaviors in mouse model.We found that DISC1 + Hits mice showed schizophrenia-like behaviors,such as hypoactivity,social withdrawal,cognitive impairment,reduced PPI,anxiety and depression-like behavior.However,antipsychotic drug olanzapine can only reverse the excessive startle reflex.The results showed that DISC1 mutation combined with Hits can induce a comprehensive and stable model of schizophrenia with negative symptoms.Part four: A schizophrenia mouse model constructed by interaction between DISC1 gene mutation and MIF gene knockoutIn order to construct a more stable and effective schizophrenia model that can be used to verify the role of interaction between gene and gene in the development of schizophrenia,we combined DISC1 gene mutation and MIF gene knockout to construct a mouse model and then evaluate the validity of mouse model by behavior detection and drug treatment.We found that mice with both MIF and DISC1 gene mutation(DISC1-MIF-/-)showed more significant schizophrenic behaviors than those with only MIF or DISC1 mutation.It is suggested that the interaction between gene and gene can enhance the validity of schizophrenia mouse model.Part five: A schizophrenia mouse model constructed by interaction between multiple gene mutations and multiple environmental insults In order to construct a more stable and effective schizophrenia model that can be used to verify the role of interaction between multiple gene mutations and multiple environmental insults in the development of schizophrenia,we used mice with both DISC1 and MIF gene mutation,combined with multiple environmental insults to construct a mouse model.Then we used behavior detection and drug treatment to evaluate the validity of mouse model.We found that DISC1-MIF-/--Hits mice did not show more significant schizophrenia-like behaviors,compared with DISC1-MIF-/-mice.The results showed that effects of environmental insults on schizophrenia development would be weaken if the effects of gene mutations were strong. |
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