Skip to main content

Advertisement

SpringerLink
Log in

Endoplasmic Reticulum in Metaplasticity: From Information Processing to Synaptic Proteostasis

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The ER (endoplasmic reticulum) is a Ca2+ reservoir and the unique protein-synthesizing machinery which is distributed throughout the neuron and composed of multiple different structural domains. One such domain is called EMC (endoplasmic reticulum membrane protein complex), pleiotropic nature in cellular functions. The ER/EMC position inside the neurons unmasks its contribution to synaptic plasticity via regulating various cellular processes from protein synthesis to Ca2+ signaling. Since presynaptic Ca2+ channels and postsynaptic ionotropic receptors are organized into the nanodomains, thus ER can be a crucial player in establishing TMNCs (transsynaptic molecular nanocolumns) to shape efficient neural communications. This review hypothesized that ER is not only involved in stress-mediated neurodegeneration but also axon regrowth, remyelination, neurotransmitter switching, information processing, and regulation of pre- and post-synaptic functions. Thus ER might not only be a protein-synthesizing and quality control machinery but also orchestrates plasticity of plasticity (metaplasticity) within the neuron to execute higher-order brain functions and neural repair.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data availability

Not applicable.

References

  1. English AR, Voeltz GK (2013) Endoplasmic Reticulum Structure and Interconnections with Other Organelles. Cold Spring Harb Perspect Biol 5:a013227–a013227

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Sala C, Segal M (2014) Dendritic Spines: The Locus of Structural and Functional Plasticity. Physiol Rev 94:141–188

    Article  CAS  PubMed  Google Scholar 

  3. Maggio N, Vlachos A (2014) Synaptic plasticity at the interface of health and disease: New insights on the role of endoplasmic reticulum intracellular calcium stores. Neuroscience 281:135–146

    Article  CAS  PubMed  Google Scholar 

  4. Karagas NE, Venkatachalam K (2019) Roles for the Endoplasmic Reticulum in Regulation of Neuronal Calcium Homeostasis. Cells 8:1232

    Article  CAS  PubMed Central  Google Scholar 

  5. Abraham WC (2008) Metaplasticity: tuning synapses and networks for plasticity. Nat Rev Neurosci 9:387

    Article  CAS  PubMed  Google Scholar 

  6. Mahajan G, Nadkarni S (2019) Intracellular calcium stores mediate metaplasticity at hippocampal dendritic spines. J Physiol 597:3473–3502

    Article  CAS  PubMed  Google Scholar 

  7. Chitwood PJ, Hegde RS (2019) The Role of EMC during Membrane Protein Biogenesis. Trends Cell Biol 29:371–384

    Article  CAS  PubMed  Google Scholar 

  8. Wideman JG (2015) The ubiquitous and ancient ER membrane protein complex (EMC): tether or not? F1000Res. 4, 624.

  9. Volkmar N et al (2019) The ER membrane protein complex promotes biogenesis of sterol-related enzymes maintaining cholesterol homeostasis J Cell Sci. 132, jcs223453.

  10. Bai L, You Q, Feng X, Kovach A, Li H (2020) Structure of the ER membrane complex, a transmembrane-domain insertase. Nature 584:475–478

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Pleiner T et al (2021) WNK1 is an assembly factor for the human ER membrane protein complex. Mol Cell 81:2693-2704.e2612

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Jan CH, Williams CC, Weissman JS (2014) Principles of ER cotranslational translocation revealed by proximity-specific ribosome profiling. Science 346:1257521–1257521

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Jonikas MC et al (2009) Comprehensive characterization of genes required for protein folding in the endoplasmic reticulum. Science 323:1693–1697

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Christianson JC et al (2011) Defining human ERAD networks through an integrative mapping strategy. Nat Cell Biol 14:93–105

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Schmid SL et al (2014) A Conserved Endoplasmic Reticulum Membrane Protein Complex (EMC) Facilitates Phospholipid Transfer from the ER to Mitochondria. PLoS Biol 12:e1001969

    Article  CAS  Google Scholar 

  16. Li Y et al (2014) A novel ER-localized transmembrane protein, EMC6, interacts with RAB5A and regulates cell autophagy. Autophagy 9:150–163

    Article  CAS  Google Scholar 

  17. Braakman I, Hebert DN (2013) Protein Folding in the Endoplasmic Reticulum. Cold Spring Harb Perspect Biol 5:a013201–a013201

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Pleiner T et al (2020) Structural basis for membrane insertion by the human ER membrane protein complex. Science 369:433–436

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Shurtleff MJ et al (2018) The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins. Elife 7:e37018

    Article  PubMed Central  PubMed  Google Scholar 

  20. Chitwood PJ, Hegde RS (2020) An intramembrane chaperone complex facilitates membrane protein biogenesis. Nature 584:630–634

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Guna A, Volkmar N, Christianson JC, Hegde RS (2018) The ER membrane protein complex is a transmembrane domain insertase. Science 359:470–473

    Article  CAS  PubMed  Google Scholar 

  22. Richard M, Boulin T, Robert VJ, Richmond JE, Bessereau JL (2013) Biosynthesis of ionotropic acetylcholine receptors requires the evolutionarily conserved ER membrane complex. Proc Natl Acad Sci USA 110:E1055-1063

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Meyer JO et al (2019) Disruption of the Key Ca2+ Binding Site in the Selectivity Filter of Neuronal Voltage-Gated Calcium Channels Inhibits Channel Trafficking. Cell Rep 29:22-33.e25

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Dolphin AC, Lee A (2020) Presynaptic calcium channels: specialized control of synaptic neurotransmitter release. Nat Rev Neurosci 21:213–229

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Schwenk J et al (2019) An ER Assembly Line of AMPA-Receptors Controls Excitatory Neurotransmission and Its Plasticity. Neuron 104:680-692.e689

    Article  CAS  PubMed  Google Scholar 

  26. Evans CS, Holzbaur ELF (2020) Quality Control in Neurons: Mitophagy and Other Selective Autophagy Mechanisms. J Mol Biol 432:240–260

    Article  CAS  PubMed  Google Scholar 

  27. Hwang J, Qi L (2018) Quality Control in the Endoplasmic Reticulum: Crosstalk between ERAD and UPR pathways. Trends Biochem Sci 43:593–605

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Verkhratsky A (2005) Physiology and Pathophysiology of the Calcium Store in the Endoplasmic Reticulum of Neurons. Physiol Rev 85:201–279

    Article  CAS  PubMed  Google Scholar 

  29. Solovyova N, Verkhratsky A (2003) Neuronal endoplasmic reticulum acts as a single functional Ca2+ store shared by ryanodine and inositol-1,4,5-trisphosphate receptors as revealed by intra-ER [Ca2+] recordings in single rat sensory neurones. Pflugers Arch 446:447–454

    Article  CAS  PubMed  Google Scholar 

  30. Brini M, Calì T, Ottolini D, Carafoli E (2014) Neuronal calcium signaling: function and dysfunction. Cell Mol Life Sci 71:2787–2814

    Article  CAS  PubMed  Google Scholar 

  31. Friel DD et al (2001) Multiple Modes of Calcium-Induced Calcium Release in Sympathetic Neurons I. J Gen Physiol 118:83–100

    Article  PubMed Central  PubMed  Google Scholar 

  32. Berridge MJ (1998) Neuronal calcium signaling. Neuron 21:13–26

    Article  CAS  PubMed  Google Scholar 

  33. Rossi AM et al (2021) Quantal Ca2+ release mediated by very few IP3 receptors that rapidly inactivate allows graded responses to IP3. Cell Rep 37:109932

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Aguado F, Espinosa-Parrilla JF, Carmona MA, Soriano E (2002) Neuronal activity regulates correlated network properties of spontaneous calcium transients in astrocytes in situ. J Neurosci 22:9430–9444

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Lezmy J et al (2021) Astrocyte Ca2+ evoked ATP release regulates myelinated axon excitability and conduction speed. Science 374, eabh2858.

  36. Ng E et al (2020) Mice lacking neuronal calcium sensor-1 show social and cognitive deficits. Behav Brain Res 381:112420

    Article  CAS  PubMed  Google Scholar 

  37. Sepehri RM, Cohen LB, Braubach O, Baker BJ (2018) Monitoring voltage fluctuations of intracellular membranes. Sci Rep 8:6911

    Article  CAS  Google Scholar 

  38. Fox PD et al (2015) Induction of stable ER-plasma-membrane junctions by Kv2.1 potassium channels. J Cell Sci 128:2096–2105

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Zomot E, Achildiev CH, Dagan I, Militsin R, Palty R (2021) Bidirectional regulation of calcium release–activated calcium (CRAC) channel by SARAF. J Cell Biol 220:e202104007

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Caldieri G et al (2017) Reticulon 3-dependent ER-PM contact sites control EGFR nonclathrin endocytosis. Science 356:617–624

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Sole L, Wagnon JL, Akin EJ, Meisler MH, Tamkun MM (2019) The MAP1B Binding Domain of Nav1.6 Is Required for Stable Expression at the Axon Initial Segment. J Neurosci 39:4238–4251

    Article  PubMed Central  PubMed  Google Scholar 

  42. Hamdan H et al (2020) Mapping axon initial segment structure and function by multiplexed proximity biotinylation. Nat Commun 11:100

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Bourke, A.M., et al. zapERtrap: A light-regulated ER release system reveals unexpected neuronal trafficking pathways. J Cell Biol 220 (2021).

  44. Schlüter A et al (2017) Structural Plasticity of Synaptopodin in the Axon Initial Segment during Visual Cortex Development Cereb Cortex 27:4662–4675

    PubMed  Google Scholar 

  45. Ozkan N et al (2021) ER - lysosome contacts at a pre-axonal region regulate axonal lysosome availability. Nat Commun 12:4493

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Lee M et al (2020) Ecm29-mediated proteasomal distribution modulates excitatory GABA responses in the developing brain. J Cell Biol 219:e201903033

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Li H.-q, Spitzer NC, (2020) Exercise enhances motor skill learning by neurotransmitter switching in the adult midbrain. Nat Commun 11:2195

    Article  CAS  Google Scholar 

  48. Guemez-Gamboa A, Xu L, Meng D, Spitzer NC (2014) Non-cell-autonomous mechanism of activity-dependent neurotransmitter switching. Neuron 82:1004–1016

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Pritchard R, Chen H, Romoli B, Spitzer NC, Dulcis D (2020) Photoperiod-induced neurotransmitter plasticity declines with aging: An epigenetic regulation? J Comp Neurol 528:199–210

    Article  CAS  PubMed  Google Scholar 

  50. Dulcis D, Jamshidi P, Leutgeb S, Spitzer NC (2013) Neurotransmitter switching in the adult brain regulates behavior. Science 340:449–453

    Article  CAS  PubMed  Google Scholar 

  51. Holliday J, Adams RJ, Sejnowski TJ, Spitzer NC (1991) Calcium-induced release of calcium regulates differentiation of cultured spinal neurons. Neuron 7:787–796

    Article  CAS  PubMed  Google Scholar 

  52. Spitzer NC, Gu X, Olson E (1994) Action potentials, calcium transients and the control of differentiation of excitable cells. Curr Opin Neurobiol 4:70–77

    Article  CAS  PubMed  Google Scholar 

  53. Gu X, Olson EC, Spitzer NC (1994) Spontaneous neuronal calcium spikes and waves during early differentiation. J Neurosci 14:6325–6335

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Gu X, Spitzer NC (1995) Distinct aspects of neuronal differentiation encoded by frequency of spontaneous Ca2+ transients. Nature 375:784–787

    Article  CAS  PubMed  Google Scholar 

  55. Gu X, Spitzer NC (1997) Breaking the Code: Regulation of Neuronal Differentiation by Spontaneous Calcium Transients. Dev Neurosci 19:33–41

    Article  CAS  PubMed  Google Scholar 

  56. Watt SD, Gu X, Smith RD, Spitzer NC (2000) Specific frequencies of spontaneous Ca2+ transients upregulate GAD 67 transcripts in embryonic spinal neurons. Mol Cell Neurosci 16:376–387

    Article  CAS  PubMed  Google Scholar 

  57. Borodinsky LN et al (2004) Activity-dependent homeostatic specification of transmitter expression in embryonic neurons. Nature 429:523–530

    Article  CAS  PubMed  Google Scholar 

  58. Cheng L et al (2005) Lbx1 and Tlx3 are opposing switches in determining GABAergic versus glutamatergic transmitter phenotypes. Nat Neurosci 8:1510–1515

    Article  CAS  PubMed  Google Scholar 

  59. Dulcis D, Spitzer NC (2008) Illumination controls differentiation of dopamine neurons regulating behaviour. Nature 456:195–201

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Vereyken EJF, Bajova H, Chow S, de Graan PNE, Gruol DL (2007) Chronic interleukin-6 alters the level of synaptic proteins in hippocampus in culture and in vivo. Eur J Neurosci 25:3605–3616

    Article  PubMed  Google Scholar 

  61. Wu Y et al (2017) Contacts between the endoplasmic reticulum and other membranes in neurons. Proc Natl Acad Sci USA 114:E4859–E4867

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Terasaki M (2018) Axonal endoplasmic reticulum is very narrow. J Cell Sci. 131, jcs210450.

  63. Groc L, Choquet D (2020) Linking glutamate receptor movements and synapse function. Science 368, eaay4631.

  64. De Gregorio C, Delgado R, Ibacache A, Sierralta J, Couve A (2017) Drosophila Atlastin in motor neurons is required for locomotion and presynaptic function. J Cell Sci 130:3507–3516

    PubMed  Google Scholar 

  65. Niu L et al (2019) Atlastin-mediated membrane tethering is critical for cargo mobility and exit from the endoplasmic reticulum. Proc Natl Acad Sci USA 116:14029–14038

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Silva M, Tran V, Marty A (2021) Calcium-dependent docking of synaptic vesicles. Trends Neurosci 44:579–592

    Article  CAS  PubMed  Google Scholar 

  67. Goel P et al (2019) A Screen for Synaptic Growth Mutants Reveals Mechanisms That Stabilize Synaptic Strength. J Neurosci 39:4051–4065

    Article  PubMed Central  PubMed  Google Scholar 

  68. de Juan-Sanz J et al (2017) Axonal Endoplasmic Reticulum Ca(2+) Content Controls Release Probability in CNS Nerve Terminals. Neuron 93(867–881):e866

    Google Scholar 

  69. Lindhout FW et al (2019) VAP-SCRN1 interaction regulates dynamic endoplasmic reticulum remodeling and presynaptic function. EMBO J 38:e101345

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Held RG et al (2020) Synapse and Active Zone Assembly in the Absence of Presynaptic Ca2+ Channels and Ca2+ Entry. Neuron 107:667-683.e669

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Chai Z et al (2017) CaV2.2 Gates Calcium-Independent but Voltage-Dependent Secretion in Mammalian Sensory Neurons. Neuron 96:1317-1326.e1314

    Article  CAS  PubMed  Google Scholar 

  72. Wu X, Cai Q, Feng Z, Zhang M (2020) Liquid-Liquid Phase Separation in Neuronal Development and Synaptic Signaling. Dev Cell 55:18–29

    Article  CAS  PubMed  Google Scholar 

  73. McDonald NA, Fetter RD, Shen K (2020) Assembly of synaptic active zones requires phase separation of scaffold molecules. Nature 588:454–458

    Article  CAS  PubMed  Google Scholar 

  74. Liang M et al (2021) Oligomerized liprin-α promotes phase separation of ELKS for compartmentalization of presynaptic active zone proteins. Cell Rep 34:108901

    Article  CAS  PubMed  Google Scholar 

  75. Caylor RC, Jin Y, Ackley BD (2013) The Caenorhabditis elegans voltage-gated calcium channel subunits UNC-2 and UNC-36 and the calcium-dependent kinase UNC-43/CaMKII regulate neuromuscular junction morphology. Neural Dev 8:10

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Kushibiki Y, Suzuki T, Jin Y, Taru H (2019) RIMB-1/RIM-Binding Protein and UNC-10/RIM Redundantly Regulate Presynaptic Localization of the Voltage-Gated Calcium Channel in Caenorhabditis elegans. J Neurosci 39:8617–8631

    Article  PubMed Central  PubMed  Google Scholar 

  77. Heine M, Heck J, Ciuraszkiewicz A, Bikbaev A (2020) Dynamic compartmentalization of calcium channel signalling in neurons. Neuropharmacology 169:107556

    Article  CAS  PubMed  Google Scholar 

  78. Dittman JS, Ryan TA (2019) The control of release probability at nerve terminals. Nat Rev Neurosci 20:177–186

    Article  CAS  PubMed  Google Scholar 

  79. Eggermann E, Bucurenciu I, Goswami SP, Jonas P (2011) Nanodomain coupling between Ca2+ channels and sensors of exocytosis at fast mammalian synapses. Nat Rev Neurosci 13:7–21

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Dolphin AC (2016) Voltage-gated calcium channels and their auxiliary subunits: physiology and pathophysiology and pharmacology. J Physiol 594:5369–5390

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Heine M, Holcman D (2020) Asymmetry Between Pre- and Postsynaptic Transient Nanodomains Shapes Neuronal Communication. Trends Neurosci 43:182–196

    Article  CAS  PubMed  Google Scholar 

  82. Rebola N et al (2019) Distinct Nanoscale Calcium Channel and Synaptic Vesicle Topographies Contribute to the Diversity of Synaptic Function. Neuron 104:693-710.e699

    Article  CAS  PubMed  Google Scholar 

  83. Lin Y et al (2019) Brain activity regulates loose coupling between mitochondrial and cytosolic Ca2+ transients. Nat Commun 10:5277

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Stein IS, Park DK, Claiborne N, Zito K (2021) Non-ionotropic NMDA receptor signaling gates bidirectional structural plasticity of dendritic spines. Cell Rep 34:108664

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Rodriguez-Moreno J et al (2020) Area-Specific Synapse Structure in Branched Posterior Nucleus Axons Reveals a New Level of Complexity in Thalamocortical Networks. J Neurosci 40:2663–2679

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. Hirabayashi Y et al (2017) ER-mitochondria tethering by PDZD8 regulates Ca2+dynamics in mammalian neurons. Science 358:623–630

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Liu H et al (2018) Spontaneous Vesicle Fusion Is Differentially Regulated at Cholinergic and GABAergic Synapses. Cell Rep 22:2334–2345

    Article  CAS  PubMed  Google Scholar 

  88. Chen C, Arai I, Satterfield R, Young SM Jr, Jonas P (2017) Synaptotagmin 2 Is the Fast Ca(2+) Sensor at a Central Inhibitory Synapse. Cell Rep 18:723–736

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Courtney NA, Briguglio JS, Bradberry MM, Greer C, Chapman ER (2018) Excitatory and Inhibitory Neurons Utilize Different Ca2+ Sensors and Sources to Regulate Spontaneous Release. Neuron 98:977-991.e975

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Masoli S, Tognolina M, Laforenza U, Moccia F, D’Angelo E (2020) Parameter tuning differentiates granule cell subtypes enriching transmission properties at the cerebellum input stage. Commun Biol 3:222

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  91. Maiolino M et al (2019) Inorganic Polyphosphate Regulates AMPA and NMDA Receptors and Protects Against Glutamate Excitotoxicity via Activation of P2Y Receptors. J Neurosci 39:6038–6048

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  92. Lee SJ et al (2020) Cell-type-specific asynchronous modulation of PKA by dopamine in learning. Nature 590:451–456

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Gomez LC et al (2020) Influence of spatially segregated IP3-producing pathways on spike generation and transmitter release in Purkinje cell axons. Proc Natl Acad Sci USA 117:11097–11108

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Tsai JW et al (2019) Transcriptional Feedback Links Lipid Synthesis to Synaptic Vesicle Pools in Drosophila Photoreceptors. Neuron 101:721-737.e724

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  95. Montgomery TR et al (2014) Axonal Targeting of the Serotonin Transporter in Cultured Rat Dorsal Raphe Neurons Is Specified by SEC24C-Dependent Export from the Endoplasmic Reticulum. J Neurosci 34:6344–6351

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Yang K et al (2021) ER exit sites in Drosophila display abundant ER-Golgi vesicles and pearled tubes but no megacarriers. Cell Rep 36:109707

    Article  CAS  PubMed  Google Scholar 

  97. Kanaani J, Patterson G, Schaufele F, Lippincott-Schwartz J, Baekkeskov S (2008) A palmitoylation cycle dynamically regulates partitioning of the GABA-synthesizing enzyme GAD65 between ER-Golgi and post-Golgi membranes. J Cell Sci 121:437–449

    Article  CAS  PubMed  Google Scholar 

  98. Dayanithi G, Forostyak O, Ueta Y, Verkhratsky A, Toescu EC (2012) Segregation of calcium signalling mechanisms in magnocellular neurones and terminals. Cell Calcium 51:293–299

    Article  CAS  PubMed  Google Scholar 

  99. Dayanithi G, Widmer H, Richard P (1996) Vasopressin-induced intracellular Ca2+ increase in isolated rat supraoptic cells. J Physiol 490:713–727

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  100. Baker RW, Hughson FM (2016) Chaperoning SNARE assembly and disassembly. Nat Rev Mol Cell Biol 17:465–479

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Tang BL (2020) Vesicle transport through interaction with t-SNAREs 1a (Vti1a)’s roles in neurons. Heliyon 6:e04600

    Article  PubMed Central  PubMed  Google Scholar 

  102. Ge Y et al (2018) Clptm1 Limits Forward Trafficking of GABAA Receptors to Scale Inhibitory Synaptic Strength. Neuron 97:596-610.e598

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  103. Bakr M et al (2021) The vSNAREs VAMP2 and VAMP4 control recycling and intracellular sorting of post-synaptic receptors in neuronal dendrites. Cell Rep 36:109678

    Article  CAS  PubMed  Google Scholar 

  104. Wang S et al (2019) Munc18 and Munc13 serve as a functional template to orchestrate neuronal SNARE complex assembly. Nat Commun. 10.

  105. Ma C, Seven SuL, AB, Xu Y, Rizo J, (2013) Reconstitution of the vital functions of Munc18 and Munc13 in neurotransmitter release. Science 339:421–425

    Article  CAS  PubMed  Google Scholar 

  106. He E et al (2017) Munc13-1 and Munc18-1 together prevent NSF-dependent de-priming of synaptic vesicles. Nat Commun 8:15915

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  107. Kraynack BA et al (2005) Dsl1p, Tip20p, and the novel Dsl3(Sec39) protein are required for the stability of the Q/t-SNARE complex at the endoplasmic reticulum in yeast. Mol Biol Cell 16:3963–3977

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  108. Spacek J, Harris KM (1997) Three-dimensional organization of smooth endoplasmic reticulum in hippocampal CA1 dendrites and dendritic spines of the immature and mature rat. J Neurosci 17:190–203

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  109. Harris KM (2020) Synaptic Odyssey. J Neurosci 40:61–80

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  110. Obashi K, Matsuda A, Inoue Y, Okabe S (2019) Precise Temporal Regulation of Molecular Diffusion within Dendritic Spines by Actin Polymers during Structural Plasticity. Cell Rep 27(1503–1515):e1508

    Google Scholar 

  111. Chirillo MA, Waters MS, Lindsey LF, Bourne JN, Harris KM (2019) Local resources of polyribosomes and SER promote synapse enlargement and spine clustering after long-term potentiation in adult rat hippocampus. Sci Rep 9:3861

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  112. Kucharz K, Krogh M, Ng AN, Toresson H (2009) NMDA receptor stimulation induces reversible fission of the neuronal endoplasmic reticulum. PLoS ONE 4:e5250

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  113. Kucharz K, Wieloch T, Toresson H (2011) Potassium-induced structural changes of the endoplasmic reticulum in pyramidal neurons in murine organotypic hippocampal slices. J Neurosci Res 89:1150–1159

    Article  CAS  PubMed  Google Scholar 

  114. Luscher C, Huber KM (2010) Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron 65:445–459

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  115. Nakamura M et al (2004) Signaling complex formation of phospholipase Cbeta4 with metabotropic glutamate receptor type 1alpha and 1,4,5-trisphosphate receptor at the perisynapse and endoplasmic reticulum in the mouse brain. Eur J Neurosci 20:2929–2944

    Article  PubMed  Google Scholar 

  116. Sanderson TM et al (2018) The Probability of Neurotransmitter Release Governs AMPA Receptor Trafficking via Activity-Dependent Regulation of mGluR1 Surface Expression. Cell Rep 25(3631–3646):e3633

    Google Scholar 

  117. Foster WJ et al (2018) Hippocampal mGluR1-dependent long-term potentiation requires NAADP-mediated acidic store Ca(2+) signaling. Sci Signal. 11, eaat9093.

  118. Ohadi D, Rangamani P (2019) Geometric Control of Frequency Modulation of cAMP Oscillations due to Calcium in Dendritic Spines. Biophys J 117:1981–1994

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  119. Pick JE, Ziff EB (2018) Regulation of AMPA receptor trafficking and exit from the endoplasmic reticulum. Mol Cell Neurosci 91:3–9

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  120. Wilkerson JR, Albanesi JP, Huber KM (2018) Roles for Arc in metabotropic glutamate receptor-dependent LTD and synapse elimination: Implications in health and disease. Semin Cell Dev Biol 77:51–62

    Article  CAS  PubMed  Google Scholar 

  121. Pick JE, Khatri L, Sathler MF, Ziff EB (2017) mGluR long-term depression regulates GluA2 association with COPII vesicles and exit from the endoplasmic reticulum. EMBO J 36:232–244

    Article  CAS  PubMed  Google Scholar 

  122. Cui-Wang T et al (2012) Local zones of endoplasmic reticulum complexity confine cargo in neuronal dendrites. Cell 148:309–321

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  123. Gonzalez-Lozano MA et al (2020) Stitching the synapse: Cross-linking mass spectrometry into resolving synaptic protein interactions. Sci Adv. 6, eaax5783.

  124. Brechet A et al (2017) AMPA-receptor specific biogenesis complexes control synaptic transmission and intellectual ability. Nat Commun 8:5910

    Article  CAS  Google Scholar 

  125. Greger IH, Khatri L, Ziff EB (2002) RNA editing at arg607 controls AMPA receptor exit from the endoplasmic reticulum. Neuron 34:759–772

    Article  CAS  PubMed  Google Scholar 

  126. Sathler M.F et al (2021) Phosphorylation of the AMPA receptor subunit GluA1 regulates clathrin-mediated receptor internalization. J Cell Sci 134, jcs257972.

  127. Tang AH et al (2016) A trans-synaptic nanocolumn aligns neurotransmitter release to receptors. Nature 536:210–214

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  128. Biederer T, Kaeser PS, Blanpied TA (2017) Transcellular Nanoalignment of Synaptic Function. Neuron 96:680–696

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  129. Miles GB, Hartley R, Todd AJ, Brownstone RM (2007) Spinal cholinergic interneurons regulate the excitability of motoneurons during locomotion. Proc Natl Acad Sci USA 104:2448–2453

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  130. Shen JL et al (2021) Vmp1, Vps13D, and Marf/Mfn2 function in a conserved pathway to regulate mitochondria and ER contact in development and disease. Curr Biol 31:3028-3039.e3027

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  131. Qin J et al (2020) Structural and mechanistic insights into secretagogin-mediated exocytosis. Proc Natl Acad Sci USA 117:6559–6570

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  132. Belenky MA, Sagiv N, Fritschy JM, Yarom Y (2003) Presynaptic and postsynaptic GABAA receptors in rat suprachiasmatic nucleus. Neuroscience 118:909–923

    Article  CAS  PubMed  Google Scholar 

  133. Salvany S et al (2019) Localization and dynamic changes of neuregulin-1 at C-type synaptic boutons in association with motor neuron injury and repair. FASEB J 33:7833–7851

    Article  CAS  PubMed  Google Scholar 

  134. Li S, Yang L, Selzer ME, Hu Y (2013) Neuronal endoplasmic reticulum stress in axon injury and neurodegeneration. Ann Neurol 74:768–777

    Article  PubMed Central  PubMed  Google Scholar 

  135. Chapman ER (2008) How does synaptotagmin trigger neurotransmitter release? Annu Rev Biochem 77:615–641

    Article  CAS  PubMed  Google Scholar 

  136. Ruhl DA et al (2019) Synaptotagmin 17 controls neurite outgrowth and synaptic physiology via distinct cellular pathways. Nat Commun 10:3532

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  137. Wild AR et al (2019) Synapse-to-Nucleus Communication through NFAT Is Mediated by L-type Ca(2+) Channel Ca(2+) Spike Propagation to the Soma. Cell Rep 26(3537–3550):e3534

    Google Scholar 

  138. Herbst WA, Martin KC (2017) Regulated transport of signaling proteins from synapse to nucleus. Curr Opin Neurobiol 45:78–84

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  139. Panayotis N, Karpova A, Kreutz MR, Fainzilber M (2015) Macromolecular transport in synapse to nucleus communication. Trends Neurosci 38:108–116

    Article  CAS  PubMed  Google Scholar 

  140. Matsumoto M et al (2019) Dynamic Changes in Ultrastructure of the Primary Cilium in Migrating Neuroblasts in the Postnatal Brain. J Neurosci 39:9967–9988

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  141. Farías GG et al (2019) Feedback-Driven Mechanisms between Microtubules and the Endoplasmic Reticulum Instruct Neuronal Polarity. Neuron 102:184-201.e188

    Article  CAS  PubMed  Google Scholar 

  142. Landínez-Macías M, Qi W, Bratus-Neuenschwander A, Müller M, Urwyler O (2021) The RNA-binding protein Musashi controls axon compartment-specific synaptic connectivity through ptp69D mRNA poly(A)-tailing. Cell Rep 36:109713

    Article  CAS  PubMed  Google Scholar 

  143. Allaway KC et al (2021) Genetic and epigenetic coordination of cortical interneuron development. Nature 597:693–697

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  144. Izadifar A et al (2021) Axon morphogenesis and maintenance require an evolutionary conserved safeguard function of Wnk kinases antagonizing Sarm and Axed. Neuron 109:2864-2883.e2868

    Article  CAS  PubMed  Google Scholar 

  145. Lewis TL, Kwon S-K, Lee A, Shaw R, Polleux F (2018) MFF-dependent mitochondrial fission regulates presynaptic release and axon branching by limiting axonal mitochondria size. Nat Commun 9:5008

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  146. Chamberlain KA et al (2021) Oligodendrocytes enhance axonal energy metabolism by deacetylation of mitochondrial proteins through transcellular delivery of SIRT2. Neuron 109:3456-3472.e3458

    Article  CAS  PubMed  Google Scholar 

  147. Guedes-Dias P, Holzbaur ELF (2019) Axonal transport: Driving synaptic function. Science 366, eaaw9997.

  148. De Vincentiis S et al (2020) Extremely Low Forces Induce Extreme Axon Growth. J Neurosci 40:4997–5007

    Article  PubMed Central  PubMed  Google Scholar 

  149. Öztürk Z, O’Kane CJ, Pérez-Moreno JJ (2020) Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration. Front Neurosci 14:48

    Article  PubMed Central  PubMed  Google Scholar 

  150. Ganguly A et al (2021) Clathrin packets move in slow axonal transport and deliver functional payloads to synapses. Neuron 109:2884-2901.e2887

    Article  CAS  PubMed  Google Scholar 

  151. Luarte A, Cornejo VH, Bertin F, Gallardo J, Couve A (2018) The axonal endoplasmic reticulum: One organelle-many functions in development, maintenance, and plasticity. Dev Neurobiol 78:181–208

    Article  CAS  PubMed  Google Scholar 

  152. Zurek N, Sparks L, Voeltz G (2011) Reticulon short hairpin transmembrane domains are used to shape ER tubules. Traffic 12:28–41

    Article  CAS  PubMed  Google Scholar 

  153. Yalcin B et al (2017) Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins. Elife 6:e23882

    Article  PubMed Central  PubMed  Google Scholar 

  154. Rao K et al (2016) Spastin, atlastin, and ER relocalization are involved in axon but not dendrite regeneration. Mol Biol Cell 27:3245–3256

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  155. Nozumi M et al (2009) Identification of functional marker proteins in the mammalian growth cone. Proc Natl Acad Sci USA 106:17211–17216

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  156. Petkovic M et al (2014) The SNARE Sec22b has a non-fusogenic function in plasma membrane expansion. Nat Cell Biol 16:434–444

    Article  CAS  PubMed  Google Scholar 

  157. Almeida RG et al (2021) Myelination induces axonal hotspots of synaptic vesicle fusion that promote sheath growth. Curr Biol 31:3743-3754.e3745

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  158. Merianda TT, Vuppalanchi D, Yoo S, Blesch A, Twiss JL (2013) Axonal transport of neural membrane protein 35 mRNA increases axon growth. J Cell Sci 126:90–102

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  159. Gonzalez C et al (2016) Axons provide the secretory machinery for trafficking of voltage-gated sodium channels in peripheral nerve. Proc Natl Acad Sci USA 113:1823–1828

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  160. Ashrafi G, de Juan-Sanz J, Farrell RJ, Ryan TA (2020) Molecular Tuning of the Axonal Mitochondrial Ca2+ Uniporter Ensures Metabolic Flexibility of Neurotransmission. Neuron 105:678-687.e675

    Article  CAS  PubMed  Google Scholar 

  161. Gomez TM, Spitzer NC (1999) In vivo regulation of axon extension and pathfinding by growth-cone calcium transients. Nature 397:350–355

    Article  CAS  PubMed  Google Scholar 

  162. Deng C et al (2021) Dynamic remodeling of ribosomes and endoplasmic reticulum in axon terminals of motoneurons. J Cell Sci. 258785.

  163. Thelen K et al (2012) Translation of the cell adhesion molecule ALCAM in axonal growth cones - regulation and functional importance. J Cell Sci 125:1003–1014

    Article  CAS  PubMed  Google Scholar 

  164. Leung LC et al (2013) Coupling of NF-protocadherin signaling to axon guidance by cue-induced translation. Nat Neurosci 16:166–173

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  165. Kim D et al (2017) Homo-trimerization is essential for the transcription factor function of Myrf for oligodendrocyte differentiation. Nucleic Acids Res 45:5112–5125

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  166. Huang H et al (2018) Interactive Repression of MYRF Self-Cleavage and Activity in Oligodendrocyte Differentiation by TMEM98 Protein. J Neurosci 38:9829–9839

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  167. Miyamoto Y et al (2018) BIG1/Arfgef1 and Arf1 regulate the initiation of myelination by Schwann cells in mice. Sci Adv. 4, eaar4471.

  168. Shen K et al (2021) Multiple sclerosis risk gene Mertk is required for microglial activation and subsequent remyelination. Cell Rep 34:108835

    Article  CAS  PubMed  Google Scholar 

  169. Forbes TA et al (2020) Environmental enrichment ameliorates perinatal brain injury and promotes functional white matter recovery. Nat Commun 11:964

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  170. Niu J et al (2021) Oligodendroglial ring finger protein Rnf43 is an essential injury-specific regulator of oligodendrocyte maturation. Neuron 109:3104-3118.e3106

    Article  CAS  PubMed  Google Scholar 

  171. Chakrabarti L, Scafidi J, Gallo V, Haydar TF (2011) Environmental enrichment rescues postnatal neurogenesis defect in the male and female Ts65Dn mouse model of Down syndrome. Dev Neurosci 33:428–441

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  172. Rattazzi L et al (2016) Impact of Enriched Environment on Murine T Cell Differentiation and Gene Expression Profile. Front Immunol 7:381

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  173. Liu J et al (2012) Impaired adult myelination in the prefrontal cortex of socially isolated mice. Nat Neurosci 15:1621–1623

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  174. Aguirre A, Dupree JL, Mangin JM, Gallo V (2007) A functional role for EGFR signaling in myelination and remyelination. Nat Neurosci 10:990–1002

    Article  CAS  PubMed  Google Scholar 

  175. Sohn J (2006) Identification of Sox17 as a Transcription Factor That Regulates Oligodendrocyte Development. J Neurosci 26:9722–9735

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  176. Yap J, Chen X, Delmotte P, Sieck GC (2020) TNFalpha selectively activates the IRE1alpha/XBP1 endoplasmic reticulum stress pathway in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 318:L483–L493

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  177. Cavone L et al (2021) A unique macrophage subpopulation signals directly to progenitor cells to promote regenerative neurogenesis in the zebrafish spinal cord. Dev Cell 56:1617-1630.e1616

    Article  CAS  PubMed  Google Scholar 

  178. de Faria O, Gonsalvez DG, Nicholson M, Xiao J (2019) Activity-dependent central nervous system myelination throughout life. J Neurochem 148:447–461

    Article  CAS  PubMed  Google Scholar 

  179. Martinez G, Khatiwada S, Costa-Mattioli M, Hetz C (2018) ER Proteostasis Control of Neuronal Physiology and Synaptic Function. Trends Neurosci 41:610–6240

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  180. Schonthal AH (2012) Endoplasmic reticulum stress: its role in disease and novel prospects for therapy. Scientifica 2012:857516

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  181. Li L et al (2021) α2δ-1 switches the phenotype of synaptic AMPA receptors by physically disrupting heteromeric subunit assembly. Cell Rep 36:109396

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  182. Saito A, Imaizumi K (2018) The broad spectrum of signaling pathways regulated by unfolded protein response in neuronal homeostasis. Neurochem Int 119:26–34

    Article  CAS  PubMed  Google Scholar 

  183. Tran N-H et al (2021) The stress-sensing domain of activated IRE1α forms helical filaments in narrow ER membrane tubes. Science 374:52–57

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  184. Hetz C, Mollereau B (2014) Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases. Nat Rev Neurosci 15:233–249

    Article  CAS  PubMed  Google Scholar 

  185. Yoon SO et al (2012) JNK3 perpetuates metabolic stress induced by Abeta peptides. Neuron 75:824–837

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  186. Hark TJ et al (2021) Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer’s Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals. Cell Syst 12:141-158.e149

    Article  CAS  PubMed  Google Scholar 

  187. Greenfield JP et al (1999) Endoplasmic reticulum and trans-Golgi network generate distinct populations of Alzheimer beta-amyloid peptides. Proc Natl Acad Sci USA 96:742–747

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  188. Chanaday NL et al (2021) Presynaptic store-operated Ca2+ entry drives excitatory spontaneous neurotransmission and augments endoplasmic reticulum stress. Neuron 109:1314-1332.e1315

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  189. Metwally E, Zhao G, Zhang YQ (2021) The calcium-dependent protease calpain in neuronal remodeling and neurodegeneration. Trends Neurosci 44:741–752

    Article  CAS  PubMed  Google Scholar 

  190. Singh N, Bartol T, Levine H, Sejnowski T, Nadkarni S (2021) Presynaptic endoplasmic reticulum regulates short-term plasticity in hippocampal synapses. Commun Biol 4:241

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  191. Gómez-Suaga P, Bravo-San Pedro JM, González-Polo RA, Fuentes JM, Niso-Santano M (2018) ER–mitochondria signaling in Parkinson’s disease. Cell Death Dis 9:337

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  192. Loncke J et al (2021) Balancing ER-Mitochondrial Ca2+ Fluxes in Health and Disease. Trends Cell Biol 31:598–612

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  193. Lee K-S et al (2018) Altered ER–mitochondria contact impacts mitochondria calcium homeostasis and contributes to neurodegeneration in vivo in disease models. Proc Natl Acad Sci USA 115:E8844–E8853

    CAS  PubMed Central  PubMed  Google Scholar 

  194. Scheiblich H et al (2021) Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes. Cell 184(5089–5106):e5021

    Google Scholar 

  195. Albert K et al (2021) Cerebral dopamine neurotrophic factor reduces α-synuclein aggregation and propagation and alleviates behavioral alterations in vivo. Mol Ther 29:2821–2840

    Article  CAS  PubMed  Google Scholar 

  196. Mallo N et al (2021) Depletion of a Toxoplasma porin leads to defects in mitochondrial morphology and contacts with the ER. J Cell Sci jcs.255299.

  197. Booth DM, Várnai P, Joseph SK, Hajnóczky G (2021) Oxidative bursts of single mitochondria mediate retrograde signaling toward the ER. Mol Cell 81:3866-3876.e3862

    Article  CAS  PubMed  Google Scholar 

  198. Mattson MP (2010) ER Calcium and Alzheimer's Disease: In a State of Flux. Sci Signal. 3, pe10-pe10.

  199. Calvo-Rodriguez M, Bacskai BJ (2021) Mitochondria and Calcium in Alzheimer’s Disease: From Cell Signaling to Neuronal Cell Death. Trends Neurosci 44:136–151

    Article  CAS  PubMed  Google Scholar 

  200. Kraus F, Roy K, Pucadyil TJ, Ryan MT (2021) Function and regulation of the divisome for mitochondrial fission. Nature 590:57–66

    Article  CAS  PubMed  Google Scholar 

  201. Horn A, Raavicharla S, Shah S, Cox D, Jaiswal JK (2020) Mitochondrial fragmentation enables localized signaling required for cell repair. J Cell Biol. 219.

  202. Takeda H et al (2021) Mitochondrial sorting and assembly machinery operates by β-barrel switching. Nature 590:163–169

    Article  CAS  PubMed  Google Scholar 

  203. Xu F et al (2020) COPII mitigates ER stress by promoting formation of ER whorls. Cell Res 31:141–156

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  204. Behesti H et al (2018) ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins. Proc Natl Acad Sci USA 115:E9717–E9726

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  205. Bowers M et al (2020) FASN-Dependent Lipid Metabolism Links Neurogenic Stem/Progenitor Cell Activity to Learning and Memory Deficits. Cell Stem Cell 27:98-109.e111

    Article  CAS  PubMed  Google Scholar 

  206. Vivas O, Tiscione SA, Dixon RE, Ory DS, Dickson EJ (2019) Niemann-Pick Type C Disease Reveals a Link between Lysosomal Cholesterol and PtdIns(4,5)P2 That Regulates Neuronal Excitability. Cell Rep 27:2636-2648.e2634

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  207. Kuijpers M et al (2021) Neuronal Autophagy Regulates Presynaptic Neurotransmission by Controlling the Axonal Endoplasmic Reticulum. Neuron 109:299-313.e299

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  208. Gold PW, Licinio J, Pavlatou MG (2012) Pathological parainflammation and endoplasmic reticulum stress in depression: potential translational targets through the CNS insulin, klotho and PPAR-γ systems. Mol Psychiatry 18:154–165

    Article  CAS  PubMed  Google Scholar 

  209. Martínez G, Khatiwada S, Costa-Mattioli M, Hetz C (2018) ER Proteostasis Control of Neuronal Physiology and Synaptic Function. Trends Neurosci 41:610–624

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  210. Martinez G et al (2016) Regulation of Memory Formation by the Transcription Factor XBP1. Cell Rep 14:1382–1394

    Article  CAS  PubMed  Google Scholar 

  211. Casas-Tinto S et al (2011) The ER stress factor XBP1s prevents amyloid-beta neurotoxicity. Hum Mol Genet 20:2144–2160

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  212. Safra M, Ben-Hamo S, Kenyon C, Henis-Korenblit S (2013) The ire-1 ER stress-response pathway is required for normal secretory-protein metabolism in C. elegans. J Cell Sci 126:4136–4146

    CAS  PubMed Central  PubMed  Google Scholar 

  213. Herranen A et al (2020) Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss. Cell Death Dis 11:100

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  214. Hu F et al (2019) Inhibition of Hsp70 Suppresses Neuronal Hyperexcitability and Attenuates Epilepsy by Enhancing A-Type Potassium Current. Cell Rep 26(168–181):e164

    Google Scholar 

  215. Tang YQ et al (2013) Auxiliary KChIP4a suppresses A-type K+ current through endoplasmic reticulum (ER) retention and promoting closed-state inactivation of Kv4 channels. J Biol Chem 288:14727–14741

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  216. Sun Z, Guerriero CJ, Brodsky JL (2021) Substrate ubiquitination retains misfolded membrane proteins in the endoplasmic reticulum for degradation. Cell Rep 36:109717

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  217. Ferris HA et al (2017) Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism. Proc Natl Acad Sci USA 114:1189–1194

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  218. Martinon F, Glimcher LH (2011) Regulation of innate immunity by signaling pathways emerging from the endoplasmic reticulum. Curr Opin Immunol 23:35–40

    Article  CAS  PubMed  Google Scholar 

  219. Mohr L et al (2021) ER-directed TREX1 limits cGAS activation at micronuclei. Mol Cell 81:724-738.e729

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  220. Slavik KM et al (2021) cGAS-like receptors sense RNA and control 3′2′-cGAMP signaling in Drosophila. Nature 597:109–113

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  221. Holleufer A et al (2021) Two cGAS-like receptors induce antiviral immunity in Drosophila. Nature 597:114–118

    Article  CAS  PubMed  Google Scholar 

  222. Hafner A-S, Donlin-Asp PG, Leitch B, Herzog E, Schuman EM (2019) Local protein synthesis is a ubiquitous feature of neuronal pre- and postsynaptic compartments. Science 364, eaau3644.

  223. Sun, C., et al. The prevalence and specificity of local protein synthesis during neuronal synaptic plasticity. Science Advances 7 (2021).

  224. Biever, A., et al. Monosomes actively translate synaptic mRNAs in neuronal processes. Science 367 (2020).

  225. Graber TE et al (2013) Reactivation of stalled polyribosomes in synaptic plasticity. Proc Natl Acad Sci USA 110:16205–16210

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  226. Fusco CM et al (2021) Neuronal ribosomes exhibit dynamic and context-dependent exchange of ribosomal proteins. Nat Commun 12:6127

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  227. Cheng LC et al (2021) Alternative 3′ UTRs play a widespread role in translation-independent mRNA association with the endoplasmic reticulum. Cell Rep 36:109407

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  228. Mitew S et al (2018) Pharmacogenetic stimulation of neuronal activity increases myelination in an axon-specific manner. Nat Commun 9:306

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  229. Ma Y, Hendershot LM (2004) ER chaperone functions during normal and stress conditions. J Chem Neuroanat 28:51–65

    Article  CAS  PubMed  Google Scholar 

  230. O’Sullivan NC, Jahn TR, Reid E, O’Kane CJ (2012) Reticulon-like-1, the Drosophila orthologue of the Hereditary Spastic Paraplegia gene reticulon 2, is required for organization of endoplasmic reticulum and of distal motor axons. Hum Mol Genet 21:3356–3365

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  231. Ramachandran KV, Margolis SS (2017) A mammalian nervous-system-specific plasma membrane proteasome complex that modulates neuronal function. Nat Struct Mol Biol 24:419–430

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  232. Kakiuchi C et al (2009) Valproate, a mood stabilizer, induces WFS1 expression and modulates its interaction with ER stress protein GRP94. PLoS ONE 4:e4134

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  233. Kucharz K, Wieloch T, Toresson H (2013) Fission and Fusion of the Neuronal Endoplasmic Reticulum. Transl Stroke Res 4:652–662

    Article  CAS  PubMed  Google Scholar 

  234. Korade Z, Heffer M, Mirnics K (2021) Medication effects on developmental sterol biosynthesis. Mol Psychiatry. https://doi.org/10.1038/s41380-021-01074-5

    Article  PubMed Central  PubMed  Google Scholar 

  235. Arnsten AFT, Datta D, Wang M (2021) The genie in the bottle-magnified calcium signaling in dorsolateral prefrontal cortex. Mol Psychiatry 26:3684–3700

    Article  CAS  PubMed  Google Scholar 

  236. Yang Y-S et al (2017) Activation of ryanodine receptors is required for PKA-mediated downregulation of A-type K+ channels in rat hippocampal neurons. J Neurosci Res 95:2469–2482

    Article  CAS  PubMed  Google Scholar 

  237. van Anken E, Bakunts A, Hu C-CA, Janssens S, Sitia R (2021) Molecular Evaluation of Endoplasmic Reticulum Homeostasis Meets Humoral Immunity. Trends Cell Biol 31:529–541

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  238. Ellgaard L, Sevier CS, Bulleid NJ (2018) How Are Proteins Reduced in the Endoplasmic Reticulum? Trends Biochem Sci 43:32–43

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  239. Perez-Alvarez A et al (2020) Endoplasmic reticulum visits highly active spines and prevents runaway potentiation of synapses. Nat Commun 11:5083

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  240. Alexia C et al (2013) The Endoplasmic Reticulum Acts as a Platform for Ubiquitylated Components of Nuclear Factor B Signaling. Sci Signal. 6, ra79-ra79.

  241. Xu F et al (2020) Development of a pH-responsive polymersome inducing endoplasmic reticulum stress and autophagy blockade. Sci Adv. 6, eabb8725.

  242. Carter SD et al (2020) Ribosome-associated vesicles: A dynamic subcompartment of the endoplasmic reticulum in secretory cells. Sci Adv. 6, eaay9572.

Download references

Acknowledgements

The author acknowledged Mohammad Azizur Rahman, Jahangirnagar University, Bangladesh, for his endeavor in manuscript drafting (< 5%) under the author's direction.

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA

    Shumsuzzaman Khan

Authors
  1. Shumsuzzaman Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.K designed the manuscript and generated the ideas. S.K wrote and edited the manuscript. S.K drew all the figures and wrote the figure legends.

Corresponding author

Correspondence to Shumsuzzaman Khan.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

The author consents to publication in this journal.

Conflict of interest

The author declares no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Highlights

EMC (endoplasmic reticulum membrane protein complex) can explain the pleiotropic nature of ER (endoplasmic reticulum) in neurons, potentiating the concept of ER metaplasticity.

ER responds to environmental stimuli or sensory processing by transferring action potentials from neuron to neuron via Ca2+-signaling and modulating the scaffolding proteins in the axon initial segment.

ER may play an essential role in neurotransmitter switching; establishment of the TMNCs (transsynaptic molecular nano-columns) between the pre-and post-synapses during synaptic potentiation.

ER may show a bias toward asynchronous neurotransmission and plays an essential function in the construction and proper functioning of active zone and PSD (postsynaptic density).

ER may involve axon regeneration to remyelination and control neurons' survival mechanisms during development and in stress conditions.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khan, S. Endoplasmic Reticulum in Metaplasticity: From Information Processing to Synaptic Proteostasis. Mol Neurobiol 59, 5630–5655 (2022). https://doi.org/10.1007/s12035-022-02916-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-022-02916-1

Keywords

Search

Navigation