PMID- 30013171 OWN - NLM STAT- MEDLINE DCOM- 20190510 LR - 20190531 IS - 1546-1726 (Electronic) IS - 1097-6256 (Print) IS - 1097-6256 (Linking) VI - 21 IP - 8 DP - 2018 Aug TI - PKCalpha integrates spatiotemporally distinct Ca(2+) and autocrine BDNF signaling to facilitate synaptic plasticity. PG - 1027-1037 LID - 10.1038/s41593-018-0184-3 [doi] AB - The protein kinase C (PKC) enzymes have long been established as critical for synaptic plasticity. However, it is unknown whether Ca(2+)-dependent PKC isozymes are activated in dendritic spines during plasticity and, if so, how this synaptic activity is encoded by PKC. Here, using newly developed, isozyme-specific sensors, we demonstrate that classical isozymes are activated to varying degrees and with distinct kinetics. PKCalpha is activated robustly and rapidly in stimulated spines and is the only isozyme required for structural plasticity. This specificity depends on a PDZ-binding motif present only in PKCalpha. The activation of PKCalpha during plasticity requires both NMDA receptor Ca(2+) flux and autocrine brain-derived neurotrophic factor (BDNF)-TrkB signaling, two pathways that differ vastly in their spatiotemporal scales of signaling. Our results suggest that, by integrating these signals, PKCalpha combines a measure of recent, nearby synaptic plasticity with local synaptic input, enabling complex cellular computations such as heterosynaptic facilitation of plasticity necessary for efficient hippocampus-dependent learning. FAU - Colgan, Lesley A AU - Colgan LA AUID- ORCID: 0000-0003-2089-6820 AD - Max Planck Florida Institute for Neuroscience, Jupiter, FL, USA. lesley.colgan@mpfi.org. FAU - Hu, Mo AU - Hu M AD - Max Planck Florida Institute for Neuroscience, Jupiter, FL, USA. FAU - Misler, Jaime A AU - Misler JA AD - Max Planck Florida Institute for Neuroscience, Jupiter, FL, USA. FAU - Parra-Bueno, Paula AU - Parra-Bueno P AD - Max Planck Florida Institute for Neuroscience, Jupiter, FL, USA. FAU - Moran, Corey M AU - Moran CM AD - Max Planck Florida Institute for Neuroscience, Jupiter, FL, USA. FAU - Leitges, Michael AU - Leitges M AD - Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway. FAU - Yasuda, Ryohei AU - Yasuda R AUID- ORCID: 0000-0001-6263-9297 AD - Max Planck Florida Institute for Neuroscience, Jupiter, FL, USA. ryohei.yasuda@mpfi.org. LA - eng GR - DP1 NS096787/NS/NINDS NIH HHS/United States GR - F32 MH101954/MH/NIMH NIH HHS/United States GR - R01 MH080047/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 - 20180716 PL - United States TA - Nat Neurosci JT - Nature neuroscience JID - 9809671 RN - 0 (Bdnf protein, mouse) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Isoenzymes) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - EC 2.7.11.13 (Prkca protein, mouse) RN - EC 2.7.11.13 (Protein Kinase C-alpha) SB - IM CIN - Nat Neurosci. 2018 Aug;21(8):1021-1022. PMID: 30013172 MH - Animals MH - Autocrine Communication/genetics/*physiology MH - Brain-Derived Neurotrophic Factor/genetics/*physiology MH - Calcium Signaling/genetics/*physiology MH - Dendritic Spines MH - Enzyme Activation MH - Hippocampus/physiology MH - Isoenzymes MH - Kinetics MH - Learning/physiology MH - Male MH - Maze Learning/physiology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Neuronal Plasticity/*physiology MH - Protein Kinase C-alpha/genetics/*physiology MH - Receptors, N-Methyl-D-Aspartate/metabolism PMC - PMC6100743 MID - NIHMS973212 COIS- The authors declare no competing financial or non-financial interests as defined by Nature Research. EDAT- 2018/07/18 06:00 MHDA- 2019/05/11 06:00 PMCR- 2019/01/16 CRDT- 2018/07/18 06:00 PHST- 2017/08/30 00:00 [received] PHST- 2018/05/29 00:00 [accepted] PHST- 2018/07/18 06:00 [pubmed] PHST- 2019/05/11 06:00 [medline] PHST- 2018/07/18 06:00 [entrez] PHST- 2019/01/16 00:00 [pmc-release] AID - 10.1038/s41593-018-0184-3 [pii] AID - 10.1038/s41593-018-0184-3 [doi] PST - ppublish SO - Nat Neurosci. 2018 Aug;21(8):1027-1037. doi: 10.1038/s41593-018-0184-3. Epub 2018 Jul 16.