Activation of PPARγ Ameliorates Spatial Cognitive Deficits through Restoring Expression of AMPA Receptors in Seipin Knock-Out Mice.
UNLABELLED
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.


SIGNIFICANCE STATEMENT
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.
['Zhou|Libin|L|', 'Chen|Tingting|T|', 'Li|Guoxi|G|', 'Wu|Chaoming|C|', 'Wang|Conghui|C|', 'Li|Lin|L|', 'Sha|Sha|S|', 'Chen|Lei|L|', 'Liu|George|G|', 'Chen|Ling|L|']
D000818:Animals D050882:CREB-Binding Protein D003072:Cognition Disorders D004195:Disease Models, Animal D004791:Enzyme Inhibitors D044388:GTP-Binding Protein gamma Subunits D005786:Gene Expression Regulation D020962:Heterotrimeric GTP-Binding Proteins D006624:Hippocampus D066298:In Vitro Techniques D017774:Long-Term Potentiation D008297:Male D018782:Maze Learning D051379:Mice D018345:Mice, Knockout D047495:PPAR gamma D018408:Patch-Clamp Techniques D018091:Receptors, AMPA D000077154:Rosiglitazone D013037:Spatial Behavior D013550:Swimming D045162:Thiazolidinediones
spatial cognitive AMPA receptor seipin peroxisome proliferator-activated receptor gamma long-term potentiation