Effects Of Mood Stabilizer On Abnormal Behaviors Of SAPAP4 Knockout Mice

Many neurological diseases usually result from synaptic dysfunction.SAPAPs(SAP90/ psd95-associated protein)family proteins,one of the core scaffold proteins of post-synaptic density(PSD),are closely related to postsynaptic signal transduction.Different subtypes(SAPAP1~4)have specific distribution in the brain,the abnormal expression of SAPAPs has been proved to be related to many brain dysfunction diseases.Our research group has constructed SAPAP4 gene whole-body knockout mice and found the mice showed long-term memory impairment,more importantly,the mice showed hyperactivity in open field test,impulse-like behavior in cliff avoidance test and antidepression in tail suspension test.The above manic-like behaviors are similar to the manic behavior phenotypes of patients with bipolar disorder.Firstly,we examined whether SAPAP4 knockout mice had other abnormal behaviors related to mania and then found that the deletion of SAPAP4 also resulted in impaired short-term memory but normal sleep and circadium rhythm in the mice.To test the predicitive validity for SAPAP4 knockout mice as mania animal model,we combined pharmacology and animal behavior tasks in this study and tested whether the FDA-approved mood stabilizers for the treatment of bipolar disorder: lithium and valproate could rescue the abnormal behaviors of SAPAP4 knockout mice.The results showed that the manic-like behavior could be partially reversed by valproate but not by lithium.In addition,dysfunction of the dopaminergic,norepinephrinergic and serotoninergic systems has been approved to be associated with manic-like behavior,our previous study found that both the selective norepinephrine-reuptake-inhibitor tomoxetine and selective serotoninergic-reuptake-inhibitor fluoxetine could reduce hyperactivity in SAPAP4 mice.So we further tested the effect of fluoxetine on other manic-like behaviors of SAPAP4 knockout mice.The results showed that fluoxetine could not alleviate the impulsive behaviors of SAPAP4 knockout mice,but intensified its antidepressant behavior.Then we detected the number of monoamine neurons in the brain of animals by using the immunohistochemical method.The results implyed that deletion of SAPAP4 did not affect the number of dopaminergic neurons in ventral tegmental area(VTA),norepinephrinergic neurons in locus locus(LC)or serotonergic neurons in nucleus raphe(DR),which suggested that the deletion of SAPAP4 does not affect the number of monoaminergic neurons but may change the sensitivity of postsynaptic monoamine neurotransmitter receptors.In this study,we combined animal behavioral,pharmacological,immunohistochemical method and other methods to systematically analyze the therapeutic efficacy of mood stablizers on minic-like behaviors of SAPAP4 knockout mice,and explored the mechanism of mania preliminarily.The results not only have important significance for elucidating the vivo physiological function of SAPAP4,but also provide a basis for further study of the mechanism of abnormal phenotypes in SAPAP4 knockout mice.SAPAP4 konckout mice showed the potential and advantages as an animal disease model of the manic phenotype in bipolar disorder,their manic-like behavioral phenotype provides a basis for further revealing the pathogenesis of bipolar disorder.