PMID- 30782829 OWN - NLM STAT- MEDLINE DCOM- 20190516 LR - 20211204 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 116 IP - 14 DP - 2019 Apr 2 TI - Synaptic retinoic acid receptor signaling mediates mTOR-dependent metaplasticity that controls hippocampal learning. PG - 7113-7122 LID - 10.1073/pnas.1820690116 [doi] AB - Homeostatic synaptic plasticity is a stabilizing mechanism engaged by neural circuits in response to prolonged perturbation of network activity. The non-Hebbian nature of homeostatic synaptic plasticity is thought to contribute to network stability by preventing "runaway" Hebbian plasticity at individual synapses. However, whether blocking homeostatic synaptic plasticity indeed induces runaway Hebbian plasticity in an intact neural circuit has not been explored. Furthermore, how compromised homeostatic synaptic plasticity impacts animal learning remains unclear. Here, we show in mice that the experience of an enriched environment (EE) engaged homeostatic synaptic plasticity in hippocampal circuits, thereby reducing excitatory synaptic transmission. This process required RARalpha, a nuclear retinoic acid receptor that doubles as a cytoplasmic retinoic acid-induced postsynaptic regulator of protein synthesis. Blocking RARalpha-dependent homeostatic synaptic plasticity during an EE experience by ablating RARalpha signaling induced runaway Hebbian plasticity, as evidenced by greatly enhanced long-term potentiation (LTP). As a consequence, RARalpha deletion in hippocampal circuits during an EE experience resulted in enhanced spatial learning but suppressed learning flexibility. In the absence of RARalpha, moreover, EE experience superactivated mammalian target of rapamycin (mTOR) signaling, causing a shift in protein translation that enhanced the expression levels of AMPA-type glutamate receptors. Treatment of mice with the mTOR inhibitor rapamycin during an EE experience not only restored normal AMPA-receptor expression levels but also reversed the increases in runaway Hebbian plasticity and learning after hippocampal RARalpha deletion. Thus, our findings reveal an RARalpha- and mTOR-dependent mechanism by which homeostatic plasticity controls Hebbian plasticity and learning. FAU - Hsu, Yu-Tien AU - Hsu YT AD - Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305-5453. AD - Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305-5453. FAU - Li, Jie AU - Li J AD - Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305-5453. AD - Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305-5453. FAU - Wu, Dick AU - Wu D AD - Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5453. FAU - Sudhof, Thomas C AU - Sudhof TC AD - Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5453; tcs1@stanford.edu luchen1@stanford.edu. AD - Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305-5453. FAU - Chen, Lu AU - Chen L AD - Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305-5453; tcs1@stanford.edu luchen1@stanford.edu. AD - Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305-5453. LA - eng GR - P50 MH086403/MH/NIMH NIH HHS/United States GR - R01 HD084215/HD/NICHD NIH HHS/United States GR - R01 MH091193/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190219 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Receptors, AMPA) RN - 0 (Receptors, Retinoic Acid) RN - 0 (Retinoic Acid Receptor alpha) RN - 5688UTC01R (Tretinoin) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM CIN - Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):6528-6530. PMID: 30872478 MH - Animals MH - Hippocampus/*metabolism MH - Homeostasis/physiology MH - Learning/*physiology MH - Long-Term Potentiation/physiology MH - Mice MH - Neuronal Plasticity/drug effects/*physiology MH - Protein Biosynthesis/drug effects MH - Receptors, AMPA/metabolism MH - Receptors, Retinoic Acid/*metabolism MH - Retinoic Acid Receptor alpha/metabolism MH - Signal Transduction/*drug effects MH - Synaptic Transmission/drug effects/physiology MH - TOR Serine-Threonine Kinases/*metabolism MH - Tretinoin/*pharmacology PMC - PMC6452649 OTO - NOTNLM OT - Hebbian plasticity OT - enriched environment OT - homeostatic synaptic plasticity OT - mTOR signaling OT - retinoic acid receptor COIS- The authors declare no conflict of interest. EDAT- 2019/02/21 06:00 MHDA- 2019/05/17 06:00 PMCR- 2019/08/19 CRDT- 2019/02/21 06:00 PHST- 2019/02/21 06:00 [pubmed] PHST- 2019/05/17 06:00 [medline] PHST- 2019/02/21 06:00 [entrez] PHST- 2019/08/19 00:00 [pmc-release] AID - 1820690116 [pii] AID - 201820690 [pii] AID - 10.1073/pnas.1820690116 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):7113-7122. doi: 10.1073/pnas.1820690116. Epub 2019 Feb 19.