title: Activation of PPARγ Ameliorates Spatial Cognitive Deficits through Restoring Expression of AMPA Receptors in Seipin Knock-Out Mice.
abstract: A characteristic phenotype of congenital generalized lipodystrophy 2 (CGL2) that is caused by loss-of-function of seipin gene is mental retardation. Here, we show that seipin deficiency in hippocampal CA1 pyramidal cells caused the reduction of peroxisome proliferator-activated receptor gamma (PPARγ). Twelve-week-old systemic seipin knock-out mice and neuronal seipin knock-out (seipin-nKO) mice, but not adipose seipin knock-out mice, exhibited spatial cognitive deficits as assessed by the Morris water maze and Y-maze, which were ameliorated by the treatment with the PPARγ agonist rosiglitazone (rosi). In addition, seipin-nKO mice showed the synaptic dysfunction and the impairment of NMDA receptor-dependent LTP in hippocampal CA1 regions. The density of AMPA-induced current (IAMPA) in CA1 pyramidal cells and GluR1/GluR2 expression were significantly reduced in seipin-nKO mice, whereas the NMDA-induced current (INMDA) and NR1/NR2 expression were not altered. Rosi treatment in seipin-nKO mice could correct the decrease in expression and activity of AMPA receptor (AMPAR) and was accompanied by recovered synaptic function and LTP induction. Furthermore, hippocampal ERK2 and CREB phosphorylation in seipin-nKO mice were reduced and this could be rescued by rosi treatment. Rosi treatment in seipin-nKO mice elevated BDNF concentration. The MEK inhibitor U0126 blocked rosi-restored AMPAR expression and LTP induction in seipin-nKO mice, but the Trk family inhibitor K252a did not. These findings indicate that the neuronal seipin deficiency selectively suppresses AMPAR expression through reducing ERK-CREB activities, leading to the impairment of LTP and spatial memory, which can be rescued by PPARγ activation.
  
  
  CONCLUSIONS
  Congenital generalized lipodystrophy 2 (CGL2), caused by loss-of-function mutation of seipin gene, is characterized by mental retardation. By the generation of systemic or neuronal seipin knock-out mice, the present study provides in vivo evidence that neuronal seipin deficiency causes deficits in spatial memory and hippocampal LTP induction. Neuronal seipin deficiency selectively suppresses AMPA receptor expression, ERK-CREB phosphorylation with the decline of PPARγ. The PPARγ agonist rosiglitazone can ameliorate spatial cognitive deficits and rescue the LTP induction in seipin knock-out mice by restoring AMPA receptor expression and ERK-CREB activities.
authors.affiliation: State Key Laboratory of Reproductive Medicine and Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Libin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Reproductive Medicine and Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Guoxi
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Endocrinology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China, and.
authors.forename: Chaoming
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Conghui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Sha
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Institute of Cardiovascular Sciences, Peking University and Key Laboratory of Cardiovascular Sciences, China Administration of Education, Beijing 100191, China lingchen@njmu.edu.cn georgeliu@bjmu.edu.cn.
authors.forename: George
authors.initials: G
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Reproductive Medicine and Department of Physiology, Nanjing Medical University, Nanjing 210029, China, lingchen@njmu.edu.cn georgeliu@bjmu.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy* / Q000235:genetics; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D044388:GTP-Binding Protein gamma Subunits; D005786:Gene Expression Regulation / Q000187:drug effects*; D020962:Heterotrimeric GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000378:metabolism*; D000077154:Rosiglitazone; D013037:Spatial Behavior / Q000187:drug effects; D013550:Swimming / Q000523:psychology; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: C115783:Bscl2 protein, mouse; D004791:Enzyme Inhibitors; D044388:GTP-Binding Protein gamma Subunits; D047495:PPAR gamma; D018091:Receptors, AMPA; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D050882:CREB-Binding Protein; D020962:Heterotrimeric GTP-Binding Proteins
keywords: AMPA receptor; long-term potentiation; peroxisome proliferator-activated receptor gamma; seipin; spatial cognitive
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