SynGAP Isoforms Differentially Regulate Synaptic Plasticity and Dendritic Development

Overview

Journal Elife

Specialty Biology

Date 2020 Jun 25

PMID 32579114

Citations 47

Authors

Yoichi Araki

Ingie Hong

Timothy R Gamache

Shaowen Ju

Leonardo Collado-Torres

Joo Heon Shin

Richard L Huganir

Affiliations

Soon will be listed here.

Abstract

SynGAP is a synaptic Ras GTPase-activating protein (GAP) with four C-terminal splice variants: α1, α2, β, and γ. Although studies have implicated in several cognitive disorders, it is not clear which SynGAP isoforms contribute to disease. Here, we demonstrate that SynGAP isoforms exhibit unique spatiotemporal expression patterns and play distinct roles in neuronal and synaptic development in mouse neurons. SynGAP-α1, which undergoes liquid-liquid phase separation with PSD-95, is highly enriched in synapses and is required for LTP. In contrast, SynGAP-β, which does not bind PSD-95 PDZ domains, is less synaptically targeted and promotes dendritic arborization. A mutation in SynGAP-α1 that disrupts phase separation and synaptic targeting abolishes its ability to regulate plasticity and instead causes it to drive dendritic development like SynGAP-β. These results demonstrate that distinct intrinsic biochemical properties of SynGAP isoforms determine their function, and individual isoforms may differentially contribute to the pathogenesis of -related cognitive disorders.

Citing Articles

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References

Lu W, Man H, Ju W, Trimble W, MacDonald J, Wang Y . Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron. 2001; 29(1):243-54. DOI: 10.1016/s0896-6273(01)00194-5. View

Hamdan F, Daoud H, Piton A, Gauthier J, Dobrzeniecka S, Krebs M . De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Biol Psychiatry. 2011; 69(9):898-901. DOI: 10.1016/j.biopsych.2010.11.015. View

Harvey C, Yasuda R, Zhong H, Svoboda K . The spread of Ras activity triggered by activation of a single dendritic spine. Science. 2008; 321(5885):136-40. PMC: 2745709. DOI: 10.1126/science.1159675. View

Sepulveda F, Bustos F, Inostroza E, A Zuniga F, Neve R, Montecino M . Differential roles of NMDA Receptor Subtypes NR2A and NR2B in dendritic branch development and requirement of RasGRF1. J Neurophysiol. 2010; 103(4):1758-70. DOI: 10.1152/jn.00823.2009. View

Writzl K, Knegt A . 6p21.3 microdeletion involving the SYNGAP1 gene in a patient with intellectual disability, seizures, and severe speech impairment. Am J Med Genet A. 2013; 161A(7):1682-5. DOI: 10.1002/ajmg.a.35930. View

Lautz J, Gniffke E, Brown E, Immendorf K, Mendel R, Smith S . Activity-dependent changes in synaptic protein complex composition are consistent in different detergents despite differential solubility. Sci Rep. 2019; 9(1):10890. PMC: 6659712. DOI: 10.1038/s41598-019-46690-y. View

Liao D, Scannevin R, Huganir R . Activation of silent synapses by rapid activity-dependent synaptic recruitment of AMPA receptors. J Neurosci. 2001; 21(16):6008-17. PMC: 6763128. View

Guo X, Hamilton P, Reish N, Sweatt J, Miller C, Rumbaugh G . Reduced expression of the NMDA receptor-interacting protein SynGAP causes behavioral abnormalities that model symptoms of Schizophrenia. Neuropsychopharmacology. 2009; 34(7):1659-72. PMC: 3690772. DOI: 10.1038/npp.2008.223. View

Chen H, Oguni A, Kennedy M . A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Neuron. 1998; 20(5):895-904. DOI: 10.1016/s0896-6273(00)80471-7. View

10.

Fu Z, Lee S, Simonetta A, Hansen J, Sheng M, Pak D . Differential roles of Rap1 and Rap2 small GTPases in neurite retraction and synapse elimination in hippocampal spiny neurons. J Neurochem. 2007; 100(1):118-31. DOI: 10.1111/j.1471-4159.2006.04195.x. View

11.

Kumar V, Zhang M, Swank M, Kunz J, Wu G . Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J Neurosci. 2005; 25(49):11288-99. PMC: 6725910. DOI: 10.1523/JNEUROSCI.2284-05.2005. View

12.

Parker M, Fryer A, Shears D, Lachlan K, McKee S, Magee A . De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability. Am J Med Genet A. 2015; 167A(10):2231-7. PMC: 4744742. DOI: 10.1002/ajmg.a.37189. View

13.

Vissers L, de Ligt J, Gilissen C, Janssen I, Steehouwer M, De Vries P . A de novo paradigm for mental retardation. Nat Genet. 2010; 42(12):1109-12. DOI: 10.1038/ng.712. View

14.

Araki Y, Zeng M, Zhang M, Huganir R . Rapid dispersion of SynGAP from synaptic spines triggers AMPA receptor insertion and spine enlargement during LTP. Neuron. 2015; 85(1):173-189. PMC: 4428669. DOI: 10.1016/j.neuron.2014.12.023. View

15.

Clement J, Aceti M, Creson T, Ozkan E, Shi Y, Reish N . Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell. 2012; 151(4):709-723. PMC: 3500766. DOI: 10.1016/j.cell.2012.08.045. View

16.

Rumbaugh G, Adams J, Kim J, Huganir R . SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons. Proc Natl Acad Sci U S A. 2006; 103(12):4344-51. PMC: 1450173. DOI: 10.1073/pnas.0600084103. View

17.

Lautz J, Brown E, Williams VanSchoiack A, Smith S . Synaptic activity induces input-specific rearrangements in a targeted synaptic protein interaction network. J Neurochem. 2018; 146(5):540-559. PMC: 6150823. DOI: 10.1111/jnc.14466. View

18.

Lin D, Makino Y, Sharma K, Hayashi T, Neve R, Takamiya K . Regulation of AMPA receptor extrasynaptic insertion by 4.1N, phosphorylation and palmitoylation. Nat Neurosci. 2009; 12(7):879-87. PMC: 2712131. DOI: 10.1038/nn.2351. View

19.

Sommer S . The importance of immune gene variability (MHC) in evolutionary ecology and conservation. Front Zool. 2005; 2:16. PMC: 1282567. DOI: 10.1186/1742-9994-2-16. View

20.

Carlisle H, Manzerra P, Marcora E, Kennedy M . SynGAP regulates steady-state and activity-dependent phosphorylation of cofilin. J Neurosci. 2008; 28(50):13673-83. PMC: 2615239. DOI: 10.1523/JNEUROSCI.4695-08.2008. View