PMID- 25934042 OWN - NLM STAT- MEDLINE DCOM- 20160809 LR - 20151102 IS - 1873-7544 (Electronic) IS - 0306-4522 (Linking) VI - 309 DP - 2015 Nov 19 TI - Ras does not contribute to the facilitation of hippocampal synaptic plasticity enabled by environmental enrichment. PG - 214-23 LID - S0306-4522(15)00393-0 [pii] LID - 10.1016/j.neuroscience.2015.04.052 [doi] AB - Environmental enrichment (EE), which mimics the wealth of sensory, motor and cognitive stimuli that arise through intense interactions with the ambient environment, results in enhanced hippocampal long-term potentiation (LTP) and spatial learning. A key molecular factor in the mediation of these changes is the brain-derived neurotrophic factor (BDNF). One of the downstream cascades that is activated by BDNF is the cascade linked to the small GTPase, Ras, that triggers mitogen-activated protein kinase (MAPK) activity and is part of the cAMP response element-binding protein (CREB) pathway that can lead to synaptic restructuring to support LTP. Here, we explored whether persistent activation of Ras in neurons further enhances LTP following EE of rodents. Immediately following weaning, transgenic mice that expressed constitutively activated neuronal Ras, or their wildtype (Wt) littermates, underwent 3weeks of constant EE. In the absence of EE, theta burst stimulation (TBS) evoked LTP in the CA1 region of transgenic mice that was not significantly different from LTP in Wts. After 3weeks of EE, hippocampal LTP was improved in Wt mice. Enriched transgenic mice showed an equivalent level of LTP to enriched Wts, but it was not significantly different from non-enriched synRas controls. Western blot analysis performed after a pull-down assay showed that non-enriched transgenic mice expressed higher Ras activity compared to non-enriched Wts. Following EE, Ras activity was reduced in transgenics to levels detected in Wts. These results show that constitutive activation of Ras does not mimic the effects of EE on LTP. In addition, EE results in an equivalent enhancement of LTP transgenics and Wts, coupled with a decrease in Ras activity to Wt levels. This suggests that permanent activation of Ras in neurons of synRas animals following EE results in an altered feedback regulation of endogenous Ras activity that is not a key factor in LTP enhancements. The maintenance of Ras within a physiological range may thus be required for the optimization of LTP in the hippocampus. CI - Copyright (c) 2015 IBRO. Published by Elsevier Ltd. All rights reserved. FAU - Novkovic, T AU - Novkovic T AD - Medical Faculty, Department of Neurophysiology, Ruhr University Bochum, 44801 Bochum, Germany; International Graduate School of Neuroscience, Ruhr University Bochum, 44801 Bochum, Germany. FAU - Heumann, R AU - Heumann R AD - International Graduate School of Neuroscience, Ruhr University Bochum, 44801 Bochum, Germany; Department of Molecular Neurobiochemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, 44801 Bochum, Germany. FAU - Manahan-Vaughan, D AU - Manahan-Vaughan D AD - Medical Faculty, Department of Neurophysiology, Ruhr University Bochum, 44801 Bochum, Germany; International Graduate School of Neuroscience, Ruhr University Bochum, 44801 Bochum, Germany. Electronic address: denise.manahan-vaughan@rub.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150429 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Actins) RN - 86-01-1 (Guanosine Triphosphate) RN - EC 3.6.5.2 (ras Proteins) SB - IM MH - Actins/metabolism MH - Animals MH - Blotting, Western MH - CA1 Region, Hippocampal/*physiology MH - Electric Stimulation/methods MH - *Environment MH - Excitatory Postsynaptic Potentials/physiology MH - Guanosine Triphosphate/metabolism MH - Housing, Animal MH - Humans MH - Long-Term Potentiation/*physiology MH - Male MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Synaptic Transmission/physiology MH - Tissue Culture Techniques MH - ras Proteins/genetics/*metabolism OTO - NOTNLM OT - BDNF OT - GTPase OT - MAP kinase OT - Ras OT - hippocampus OT - synaptic plasticity EDAT- 2015/05/03 06:00 MHDA- 2016/08/10 06:00 CRDT- 2015/05/03 06:00 PHST- 2015/01/09 00:00 [received] PHST- 2015/03/25 00:00 [revised] PHST- 2015/04/21 00:00 [accepted] PHST- 2015/05/03 06:00 [entrez] PHST- 2015/05/03 06:00 [pubmed] PHST- 2016/08/10 06:00 [medline] AID - S0306-4522(15)00393-0 [pii] AID - 10.1016/j.neuroscience.2015.04.052 [doi] PST - ppublish SO - Neuroscience. 2015 Nov 19;309:214-23. doi: 10.1016/j.neuroscience.2015.04.052. Epub 2015 Apr 29.