【摘 要】
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Neuronal polarity is involved in multiple developmental stages,including cortical neuron migration,multipolar-to-bipolar transition,axon initiation,apical/basal dendrite differentiation,and spine formation.All of these processes are associated with the cy
【机 构】
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Peking University Institute of Mental Health, Peking University Sixth Hospital, Beijing 100191, Chin
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Neuronal polarity is involved in multiple developmental stages,including cortical neuron migration,multipolar-to-bipolar transition,axon initiation,apical/basal dendrite differentiation,and spine formation.All of these processes are associated with the cytoskeleton and are regulated by precise timing and by controlling gene expression.The P-Rexl (phosphatidylinositol3,4,5-trisphosphate dependent Rac exchange factor 1) gene for example,is known to be important for cytoskeletal reorganization,cell motility,and migration.Deficiency of P-Rexl protein leads to abnormal neuronal migration and synaptic plasticity,as well as autism-related behaviors.Nonetheless,the effects of P-Rexl overexpression on neuronal development and higher brain functions remain unclear.In the present study,we explored the effect of P-Rexl overexpression on cerebral development and psychosis-related behaviors in mice.In utero electroporation at embryonic day 14.5 was used to assess the influence of P-Rex1 overexpression on cell polarity and migration.Primary neuron culture was used to explore the effects of P-Rexl overexpression on neuritogenesis and spine morphology.In addition,P-Rexl overexpression in the medial prefrontal cortex (mPFC) of mice was used to assess psychosis-related behaviors.We found that P-Rexl overexpression led to aberrant polarity and inhibited the multipolar-to-bipolar transition,leading to abnormal neuronal migration.In addition,P-Rexl overexpression affected the early development of neurons,manifested as abnormal neurite initiation with cytoskeleton change,reduced the axon length and dendritic complexity,and caused excessive lamellipodia in primary neuronal culture.Moreover,P-Rexl overexpression decreased the density of spines with increased height,width,and head area in vitro and in vivo.Behavioral tests showed that P-Rexl overexpression in the mouse mPFC caused anxiety-like behaviors and a sensorimotor gating deficit.The appropriate P-Rexl level plays a critical role in the developing cerebral cortex and excessive P-Rexl might be related to psychosis-related behaviors.
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