RGS14 Restricts Plasticity in Hippocampal CA2 by Limiting Postsynaptic Calcium Signaling
Paul R Evans, Paula Parra-Bueno, Michael S Smirnov, Daniel J Lustberg, Serena M Dudek, John R Hepler, Ryohei Yasuda, Paul R Evans, Paula Parra-Bueno, Michael S Smirnov, Daniel J Lustberg, Serena M Dudek, John R Hepler, Ryohei Yasuda
Abstract
Pyramidal neurons in hippocampal area CA2 are distinct from neighboring CA1 in that they resist synaptic long-term potentiation (LTP) at CA3 Schaffer collateral synapses. Regulator of G protein signaling 14 (RGS14) is a complex scaffolding protein enriched in CA2 dendritic spines that naturally blocks CA2 synaptic plasticity and hippocampus-dependent learning, but the cellular mechanisms by which RGS14 gates LTP are largely unexplored. A previous study has attributed the lack of plasticity to higher rates of calcium (Ca2+) buffering and extrusion in CA2 spines. Additionally, a recent proteomics study revealed that RGS14 interacts with two key Ca2+-activated proteins in CA2 neurons: calcium/calmodulin and CaMKII. Here, we investigated whether RGS14 regulates Ca2+ signaling in its host CA2 neurons. We found that the nascent LTP of CA2 synapses caused by genetic knockout (KO) of RGS14 in mice requires Ca2+-dependent postsynaptic signaling through NMDA receptors, CaMK, and PKA, revealing similar mechanisms to those in CA1. We report that RGS14 negatively regulates the long-term structural plasticity of dendritic spines of CA2 neurons. We further show that wild-type (WT) CA2 neurons display significantly attenuated spine Ca2+ transients during structural plasticity induction compared with the Ca2+ transients from CA2 spines of RGS14 KO mice and CA1 controls. Finally, we demonstrate that acute overexpression of RGS14 is sufficient to block spine plasticity, and elevating extracellular Ca2+ levels restores plasticity to RGS14-expressing neurons. Together, these results demonstrate for the first time that RGS14 regulates plasticity in hippocampal area CA2 by restricting Ca2+ elevations in CA2 spines and downstream signaling pathways.
Keywords: Calcium; Dendritic Spines; Hippocampal CA2; LTP; RGS14; Spine Plasticity.
Figures
References
- Abel T, Nguyen PV, Barad M, Deuel TA, Kandel ER, Bourtchouladze R (1997) Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell 88:615–626.
- Aoyagi Y, et al. (2015) A rapid optical clearing protocol using 2,2′-thiodiethanol for microscopic observation of fixed mouse brain. PLoS One 10:e0116280. 10.1371/journal.pone.0116280
- Carstens KE, Phillips ML, Pozzo-Miller L, Weinberg RJ, Dudek SM (2016) Perineuronal nets suppress plasticity of excitatory synapses on CA2 pyramidal neurons. J Neurosci 36:6312–6320. 10.1523/JNEUROSCI.0245-16.2016
- Caruana D. a, Alexander GM, Dudek SM (2012) New insights into the regulation of synaptic plasticity from an unexpected place: hippocampal area CA2. Learn Mem 19:391–400. 10.1101/lm.025304.111
- Cembrowski MS, Wang L, Sugino K, Shields BC, Spruston N (2016) Hipposeq: a comprehensive RNA-seq database of gene expression in hippocampal principal neurons. eLife 5:e14997. 10.7554/eLife.14997
- Cho H, Kozasa T, Takekoshi K, De Gunzburg J, Kehrl JH (2000) RGS14, a GTPase-activating protein for Gialpha, attenuates Gialpha- and G13alpha-mediated signaling pathways. Mol Pharmacol 58:569–576.
- Dudek SM, Alexander GM, Farris S (2016) Rediscovering area CA2: unique properties and functions. Nat Rev Neurosci 17:89–102. 10.1038/nrn.2015.22
- Evans PR, Gerber KJ, Dammer EB, Duong DM, Goswami D, Lustberg DJ, Zou J, Yang JJ, Dudek SM, Griffin PR, Seyfried NT, Hepler JR (2018) Interactome analysis reveals regulator of G protein signaling 14 (RGS14) is a novel calcium/calmodulin (Ca2+/CaM) and CaM kinase II (CaMKII) binding partner. J Proteome Res 17:1700–1711. 10.1021/acs.jproteome.8b00027.
- Evans PR, Dudek SM, Hepler JR (2015) Regulator of G protein signaling 14: a molecular brake on synaptic plasticity linked to learning and memory. Prog Mol Biol Transl Sci 133:169–206. 10.1016/bs.pmbts.2015.03.006
- Evans PR, Lee SE, Smith Y, Hepler JR (2014) Postnatal developmental expression of regulator of G protein signaling 14 (RGS14) in the mouse brain. J Comp Neur 522:186–203. 10.1002/cne.23395
- Harvey CD, Yasuda R, Zhong H, Svoboda K (2008) The spread of Ras activity triggered by activation of a single dendritic spine. Science 321:136–140. 10.1126/science.1159675
- Hollinger S, Ramineni S, Hepler JR (2003) Phosphorylation of RGS14 by protein kinase a potentiates its activity toward Gαi. Biochemistry 42:811–819. 10.1021/bi026664y
- Hollinger S, Taylor JB, Goldman EH, Hepler JR (2001) RGS14 is a bifunctional regulator of Galphai/o activity that exists in multiple populations in brain. J Neurochem 79:941–949.
- Kiel C, Wohlgemuth S, Rousseau F, Schymkowitz J, Ferkinghoff-Borg J, Wittinghofer F, Serrano L (2005) Recognizing and defining true Ras binding domains II: in silico prediction based on homology modelling and energy calculations. J Mol Biol 348:759–775. 10.1016/j.jmb.2005.02.046
- Lee S-JR, Escobedo-Lozoya Y, Szatmari EM, Yasuda R (2009) Activation of CaMKII in single dendritic spines during long-term potentiation. Nature 458:299–304. 10.1038/nature07842
- Lee SE, Simons SB, Heldt SA, Zhao M, Schroeder JP, Vellano CP, Cowan DP, Ramineni S, Yates CK, Feng Y, Smith Y, Sweatt JD, Weinshenker D, Ressler KJ, Dudek SM, Hepler JR (2010) RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory. Proc Natl Acad Sci U S A 107:16994–16998. 10.1073/pnas.1005362107
- Lein ES, et al. (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445:168–176. 10.1038/nature05453
- Lein ES, Callaway EM, Albright TD, Gage FH (2005) Redefining the boundaries of the hippocampal CA2 subfield in the mouse using gene expression and 3-dimensional reconstruction. J Comp Neur 485:1–10. 10.1002/cne.20426
- Lynch G, Larson J, Kelso S, Barrionuevo G, Schottler F (1983) Intracellular injections of EGTA block induction of hippocampal long-term potentiation. Nature 305:719–721.
- Malenka RC, Kauer JA, Perkel DJ, Mauk MD, Kelly PT, Nicoll RA, Waxham MN (1989) An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature 340:554–557. 10.1038/340554a0
- Malenka RC, Kauer JA, Zucker RS, Nicoll RA (1988) Postsynaptic calcium is sufficient for potentiation of hippocampal synaptic transmission. Science 242:81–84.
- Matsuzaki M, Honkura N, Ellis-Davies GCR, Kasai H (2004) Structural basis of long-term potentiation in single dendritic spines. Nature 429:761–766. 10.1038/nature02617
- McAllister AK (2000) Biolistic transfection of neurons. Sci STKE 2000:pl1. 10.1126/stke.2000.51.pl1
- Nishiyama J, Yasuda R (2015) Biochemical computation for spine structural plasticity. Neuron 87:63–75. 10.1016/j.neuron.2015.05.043
- Otmakhova NA, Otmakhov N, Mortenson LH, Lisman JE (2000) Inhibition of the cAMP pathway decreases early long-term potentiation at CA1 hippocampal synapses. J Neurosci 20:4446–4451.
- Pagani JH, Zhao M, Cui Z, Avram SKW, Caruana DA, Dudek SM, Young WS (2015) Role of the vasopressin 1b receptor in rodent aggressive behavior and synaptic plasticity in hippocampal area CA2. Mol Psychiatry 20:490–499. 10.1038/mp.2014.47
- Shu F, Ramineni S, Hepler JR (2010) RGS14 is a multifunctional scaffold that integrates G protein and Ras/Raf MAPkinase signalling pathways. Cell Signal 22:366–376. 10.1016/j.cellsig.2009.10.005
- Simons SB, Caruana DA, Zhao M, Dudek SM (2012) Caffeine-induced synaptic potentiation in hippocampal CA2 neurons. Nat Neurosci 15:23–25. 10.1038/nn.2962
- Simons SB, Escobedo Y, Yasuda R, Dudek SM (2009) Regional differences in hippocampal calcium handling provide a cellular mechanism for limiting plasticity. Proc Natl Acad Sci U S A 106:14080–14084. 10.1073/pnas.0904775106
- Skeberdis VA, Chevaleyre V, Lau CG, Goldberg JH, Pettit DL, Suadicani SO, Lin Y, Bennett MVL, Yuste R, Castillo PE, Zukin RS (2006) Protein kinase A regulates calcium permeability of NMDA receptors. Nat Neurosci 9:501–510. 10.1038/nn1664
- Smirnov MS, Evans PR, Garrett TR, Yan L, Yasuda R, Juskaitis R (2017) Automated remote focusing, drift correction, and photostimulation to evaluate structural plasticity in dendritic spines. PLoS One 12:e0170586 10.1371/journal.pone.0170586
- Squires KE, Gerber KJ, Pare J-F, Branch MR, Smith Y, Hepler JR (2017) Regulator of G protein signaling 14 (RGS14) is expressed pre- and postsynaptically in neurons of hippocampus, basal ganglia, and amygdala of monkey and human brain. Brain Struct Funct 223:233–253. 10.1007/s00429-017-1487-y. [Epub ahead of print] PMID: 28776200.
- Srinivas KV, Buss EW, Sun Q, Santoro B, Takahashi H, Nicholson DA, Siegelbaum SA (2017) The dendrites of CA2 and CA1 pyramidal neurons differentially regulate information flow in the cortico-hippocampal circuit. J Neurosci 37:3276–3293. 10.1523/JNEUROSCI.2219-16.2017
- Stoppini L, Buchs PA, Muller D (1991) A simple method for organotypic cultures of nervous tissue. J Neurosci Methods 37:173–182.
- Tang S, Yasuda R (2017) Imaging ERK and PKA activation in single dendritic spines during structural plasticity. Neuron 93:1315–1324.e3. 10.1016/j.neuron.2017.02.032
- Traver S, Bidot C, Spassky N, Baltauss T, De Tand MF, Thomas JL, Zalc B, Janoueix-Lerosey I, Gunzburg JD (2000) RGS14 is a novel Rap effector that preferentially regulates the GTPase activity of galphao. Biochem J 350:19–29. 10.1042/bj3500019
- Vellano CP, Brown NE, Blumer JB, Hepler JR (2013) Assembly and function of the regulator of G protein signaling 14 RGS14·H-Ras signaling complex in live cells are regulated by Gαi1 and Gαi-linked G protein-coupled receptors. J Biol Chem 288:3620–3631. 10.1074/jbc.M112.440057
- Yasuda R, Harvey CD, Zhong H, Sobczyk A, van Aelst L, Svoboda K (2006) Supersensitive Ras activation in dendrites and spines revealed by two-photon fluorescence lifetime imaging. Nat Neurosci 9:283–291. 10.1038/nn1635
- Yasuda R, Nimchinsky EA, Scheuss V, Pologruto TA, Oertner TG, Sabatini BL, Svoboda K (2004) Imaging calcium concentration dynamics in small neuronal compartments. Sci Signal 2004:pI5. 10.1126/stke.2192004pl5
- Zhao M, Choi Y-S, Obrietan K, Dudek SM (2007) Synaptic plasticity (and the lack thereof) in hippocampal CA2 neurons. J Neurosci 27:12025–12032. 10.1523/JNEUROSCI.4094-07.2007
Source: PubMed