{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T19:56:15Z","timestamp":1767210975069},"reference-count":59,"publisher":"Society for Neuroscience","issue":"4","license":[{"start":{"date-parts":[[2016,7,27]],"date-time":"2016-07-27T00:00:00Z","timestamp":1469577600000},"content-version":"vor","delay-in-days":182,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2016,1,27]]},"abstract":"<jats:p>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 (PPAR\u03b3). Twelve-week-old systemic<jats:italic>seipin<\/jats:italic>knock-out mice and neuronal<jats:italic>seipin<\/jats:italic>knock-out (<jats:italic>seipin<\/jats:italic>-nKO) mice, but not adipose<jats:italic>seipin<\/jats:italic>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 PPAR\u03b3 agonist rosiglitazone (rosi). In addition,<jats:italic>seipin<\/jats:italic>-nKO mice showed the synaptic dysfunction and the impairment of NMDA receptor-dependent LTP in hippocampal CA1 regions. The density of AMPA-induced current (<jats:italic>I<\/jats:italic><jats:sub>AMPA<\/jats:sub>) in CA1 pyramidal cells and GluR1\/GluR2 expression were significantly reduced in<jats:italic>seipin<\/jats:italic>-nKO mice, whereas the NMDA-induced current (<jats:italic>I<\/jats:italic><jats:sub>NMDA<\/jats:sub>) and NR1\/NR2 expression were not altered. Rosi treatment in<jats:italic>seipin<\/jats:italic>-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<jats:italic>seipin<\/jats:italic>-nKO mice were reduced and this could be rescued by rosi treatment. Rosi treatment in<jats:italic>seipin<\/jats:italic>-nKO mice elevated BDNF concentration. The MEK inhibitor U0126 blocked rosi-restored AMPAR expression and LTP induction in<jats:italic>seipin<\/jats:italic>-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 PPAR\u03b3 activation.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>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<jats:italic>seipin<\/jats:italic>knock-out mice, the present study provides<jats:italic>in vivo<\/jats:italic>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 PPAR\u03b3. The PPAR\u03b3 agonist rosiglitazone can ameliorate spatial cognitive deficits and rescue the LTP induction in<jats:italic>seipin<\/jats:italic>knock-out mice by restoring AMPA receptor expression and ERK-CREB activities.<\/jats:p>","DOI":"10.1523\/jneurosci.3280-15.2016","type":"journal-article","created":{"date-parts":[[2016,1,27]],"date-time":"2016-01-27T17:47:44Z","timestamp":1453916864000},"page":"1242-1253","source":"Crossref","is-referenced-by-count":41,"title":["Activation of PPAR\u03b3 Ameliorates Spatial Cognitive Deficits through Restoring Expression of AMPA Receptors in Seipin Knock-Out 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