ABSTRACT
Neuronal activity regulates spatial distribution of the SUMOylation system in cytosolic and dendritic sites, which has been implicated in learning, memory, and underlying synaptic structural and functional remodeling in the hippocampus. However, the functional target proteins for activated small ubiquitin-like modifiers (SUMOs) and downstream molecular consequences behind long-term potentiation (LTP) of synaptic plasticity remain to be elucidated. In this study, we showed that N-methyl-D-aspartate receptor-mediated neuronal activity induced the covalent modification of cytosolic Akt1 by small ubiquitin-like modifier 1 (SUMO1) in rat cortical and hippocampal CA1 neurons. Protein inhibitor of activated STAT3 (PIAS3) was involved in the activity-induced Akt1 SUMO1-ylation, and K64 and K276 residues were major SUMOylated sites. Importantly, Akt1 SUMOylation at K64 and K276 enhanced its enzymatic activity and facilitated T308 phosphorylation. Furthermore, the N-terminal SAP domain of PIAS3 bound Akt1 directly. The disruption of Akt1-PIAS3 interaction by Tat-SAP, a synthetic Tat-fused cell-permeable peptide containing PIAS3 SAP domain, inhibited neuronal activity-induced Akt1 SUMOylation and impaired LTP expression and late phase LTP maintenance in the hippocampus. Correlatedly, Tat-SAP not only blocked the LTP-related extracellular signal-regulated kinase (ERK)1/2-Elk-1-brain-derived neurotrophic factor (BDNF)/Arc signaling, but also disrupted mammalian target of rapamycin (mTOR)-eIF4E-binding protein 1 (4E-BP1) pathway. These findings reveal an activity-induced Akt1 SUMOylation by PIAS3 that contributes to ERK1/2-BDNF/Arc and mTOR-4E-BP1 cascades, and in turn, long-lasting excitatory synaptic responses.
Subject(s)
Hippocampus , Molecular Chaperones/metabolism , Neurons , Protein Inhibitors of Activated STAT/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Synaptic Transmission , Animals , Cells, Cultured , Female , HEK293 Cells , Hippocampus/cytology , Hippocampus/metabolism , Humans , Male , Neurons/cytology , Neurons/metabolism , Phosphorylation , Primary Cell Culture , Rats , Rats, Sprague-Dawley , SumoylationABSTRACT
BACKGROUND: In our previous study, we had identified strong associations between dyslipidemia and acute-phase schizophrenia during the 3-week study period. In this study, we further investigated the correlations between weight changes and lipid changes during this short period in Taiwan. METHODS: During a 1-year period, the data of age, body mass index, antipsychotic drugs and fasting blood samples for serum lipid profiles were collected at baseline and endpoint of 3 weeks. The antipsychotic drugs used include haloperidol, loxapine, sulpiride, olanzapine, risperidone, and clozapine. RESULTS: A total of 97 schizophrenia patients were enrolled in this study. The authors found that most antipsychotic drugs showed increased weight changes in Taiwanese patients. Using linear regression, the authors also found that the weight changes in patients taking clozapine had significantly negative correlation with HDL changes during the 3-week study period. However, no significant correlations between weight changes and lipid changes were noted in patients using other antipsychotic drugs. CONCLUSIONS: The results of this study showed that most antipsychotic drugs showed increased weight changes and schizophrenia patients using clozapine might have negative correlations between weight changes and HDL changes during a very short period. However, due to the limitation of the sample size, larger samples are needed to prove the results after controlling confounding factors.