Molecular Mechanisms Underlying Abnormal Behaviors Of SAPAP4 Knockout Mice

SAPAP(SAP90/PSD95 associated proteins)is a family of scaffold proteins localized in the postsynaptic density(PSD),which is believed to play important roles in the function of synapses,although the molecular mechanism is still unclear.SAPAP4 protein,one of the isoform of the SAPAP protein family,is widely distributed in the prefrontal cortex,striatum and cerebellum region whose activities are involved in execution and inhibition.The previous study in our lab has found that the SAPAP4 knock-out mice exhibited hyperactivity in the open field test,which could be rescued by atomoxetine(one of the clinical medication for attention-deficit hyperactivity disorder).However,the molecular mechanism of the SAPAP4knock-out leading to these abnormal behaviors is still unknown.The current study was aimed to further characterize the behaviors of the SAPAP4 knock-out mice,specifically those related with the activities of prefrontal cortex.In addition,by combining pharmacological and biochemical approach,we tried to explore the molecular mechanisms of SAPAP4 leading to these behaviors.We found out that SAPAP4 knock-out mice showed excessive impulsive behavior in the cliff avoidance task,as well as hyperactivity in tail suspension test.Both deficits could not be rescued by atomoxetine.Although the amount of neurotransmitters including dopamine,norepinephrine and serotonin in the medial prefrontal cortex(mPFC)showed no significant difference compared to that of wild type littermates through high performance liquid chromatograohy(HPLC)analysis,several postsynaptic proteins including PSD95,GluR1,GluR2 and mGluR5 were significantly decreased in PSD region of SAPAP4 knock-out mice,however the amount of GluR1 and GluR2 were increased in the total protein lysate.Interestingly,postsynaptic Shank proteins were significantly increased in knock-out mice.Furthermore,we discovered the decreased amount of spine density in mPFC of SAPAP4 knock-out mice by Golgi staining with no apparent change in morphology ofpostsynaptic density(PSD)in SAPAP4 knock-out mice through eletronic microscope observation.Taken together,our study suggested that the hyperactivity and excessive impulsive behavior observed in our SAPAP4 knock-out mice may due to the decreased level of AMPAR and mGluR5 receptors in prefrontal cortex,which were also found in some ADHD patients or animal models.Therefore,our SAPAP4knock-out mice may serve as a potential animal model for attention deficit hyperactivity disorder or bipolar disorder disease.