Abstract
Environmental light significantly influences neural development, yet the specific mechanisms underlying the effects of prolonged visual experience on homeostatic synaptic scaling remain unclear. Using manipulated ambient light conditions, we observed reduced mEPSC amplitudes and visually evoked responses in 20 hr light/4 hr dark (20LE) compared to a standard 12 hr light/12 hr dark (12LE) reared Xenopus laevis tadpoles. Prolonged light exposure accelerates the developmental decline of glutamatergic synaptic transmission via Rab5c-dependent endocytosis of AMPA receptor (AMPAR) subunits GluA1 and GluA2. The synaptic changes were accompanied by increased intrinsic neuronal excitability, but unchanged presynaptic release probability, and coincided with altered dendritic architecture. Notably, synaptic transmission and AMPAR expression were reversible upon re-exposure to standard 12LE conditions. Class I HDAC-mediated histone acetylation links epigenetic regulation to sustained AMPAR downregulation, revealing a two-stage process in which prolonged visual experience drives homeostatic synaptic downscaling through coordinated transcriptional/epigenetic mechanism and Rab5c-mediated trafficking.
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Data availability
All data and materials generated in this study are available in the main text and supplementary materials. Source data for all graphs can be found in the Supplementary Data. All sequencing data have been deposited at the NCBI Sequence Read Archive under accession no. PRJNA1375510.
References
Shen, W. H. et al. Acute synthesis of CPEB is required for plasticity of visual avoidance behavior in Xenopus. Cell Rep. 6, 737–747 (2014).
Ruan, H. Z. et al. Visual experience dependent regulation of neuronal structure and function by histone deacetylase 1 in developing Xenopus tectum in vivo. Dev. Neurobiol. 77, 947–962 (2017).
Shen, W. H., Da Silva, J. S., He, H. Y. & Cline, H. T. Type A GABA-receptor-dependent synaptic transmission sculpts dendritic arbor structure in Xenopus tadpoles in vivo. J. Neurosci. 29, 5032–5043 (2009).
Gao, M. et al. A specific requirement of Arc/Arg3.1 for visual experience-induced homeostatic synaptic plasticity in mouse primary visual cortex. J. Neurosci. 30, 7168–7178 (2010).
Xu, H., Khakhalin, A. S., Nurmikko, A. V. & Aizenman, C. D. Visual experience-dependent maturation of correlated neuronal activity patterns in a developing visual system. J. Neurosci. 31, 8025–8036 (2011).
He, H. Y., Shen, W. H., Zheng, L. J., Guo, X. & Cline, H. T. Excitatory synaptic dysfunction cell-autonomously decreases inhibitory inputs and disrupts structural and functional plasticity. Nat. Commun. 9, 2893 (2018).
Desai, N. S., Cudmore, R. H., Nelson, S. B. & Turrigiano, G. G. Critical periods for experience-dependent synaptic scaling in visual cortex. Nat. Neurosci. 5, 783–789 (2002).
Aizenman, C. D., Muñoz-Elı́as, G. & Cline, H. T. Visually driven modulation of glutamatergic synaptic transmission is mediated by the regulation of intracellular polyamines. Neuron 34, 623–634 (2002).
Nataraj, K., Le Roux, N., Nahmani, M., Lefort, S. & Turrigiano, G. Visual deprivation suppresses L5 pyramidal neuron excitability by preventing the induction of intrinsic plasticity. Neuron 68, 750–762 (2010).
Haas, K., Li, J. L. & Cline, H. T. AMPA receptors regulate experience-dependent dendritic arbor growth. Proc. Natl. Acad. Sci. USA 103, 12127–12131 (2006).
Turrigiano, G. G. Homeostatic plasticity in neuronal networks: the more things change, the more they stay the same. Trends Neurosci. 22, 221–227 (1999).
Pratt, K. G. & Aizenman, C. D. Homeostatic regulation of intrinsic excitability and synaptic transmission in a developing visual circuit. J. Neurosci. 27, 8268–8277 (2007).
Shen, W. H., McKeown, C. R., Demas, J. A. & Cline, H. T. Inhibition to excitation ratio regulates visual system responses and behavior in vivo. J. Neurophysiol. 106, 2285–2302 (2011).
Hartman, K. N., Pal, S. K., Burrone, J. & Murthy, V. N. Activity-dependent regulation of inhibitory synaptic transmission in hippocampal neurons. Nat. Neurosci. 9, 642–649 (2006).
Gainey, M. A., Tatavarty, V., Nahmani, M., Lin, H. & Turrigiano, G. G. Activity-dependent synaptic GRIP1 accumulation drives synaptic scaling up in response to action potential blockade. Proc. Natl. Acad. Sci. USA 112, E3590–E3599 (2015).
Keck, T. et al. Synaptic scaling and homeostatic plasticity in the mouse visual cortex in vivo. Neuron 80, 327–334 (2013).
Cingolani, L. A. et al. Activity-dependent regulation of synaptic AMPA receptor composition and abundance by β3 integrins. Neuron 58, 749–762 (2008).
Aizenman, C. D., Akerman, C. J., Jensen, K. R. & Cline, H. T. Visually driven regulation of intrinsic neuronal excitability improves stimulus detection in vivo. Neuron 39, 831–842 (2003).
Fong, M. F., Newman, J. P., Potter, S. M. & Wenner, P. Upward synaptic scaling is dependent on neurotransmission rather than spiking. Nat. Commun. 6, 6339 (2015).
Turrigiano, G. G. The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135, 422–435 (2008).
Bredt, D. S. & Nicoll, R. A. AMPA receptor trafficking at excitatory synapses. Neuron 40, 361–379 (2003).
Kessels, H. W. & Malinow, R. Synaptic AMPA receptor plasticity and behavior. Neuron 61, 340–350 (2009).
Wu, G. Y., Malinow, R. & Cline, H. T. Maturation of a central glutamatergic synapse. Science 274, 972–976 (1996).
Carroll, R. C. et al. Dynamin-dependent endocytosis of ionotropic glutamate receptors. Proc. Natl. Acad. Sci. USA 96, 14112–14117 (1999).
Henley, J. M., Barker, E. A. & Glebov, O. O. Routes, destinations and delays: recent advances in AMPA receptor trafficking. Trends Neurosci. 34, 258–268 (2011).
Zheng, N., Jeyifous, O., Munro, C., Montgomery, J. M. & Green, W. N. Synaptic activity regulates AMPA receptor trafficking through different recycling pathways. eLife 4, e06878 (2015).
Shen, W. H. et al. Activity-induced rapid synaptic maturation mediated by presynaptic Cdc42 signaling. Neuron 50, 401–414 (2006).
Plant, K. et al. Transient incorporation of native GluR2-lacking AMPA receptors during hippocampal long-term potentiation. Nat. Neurosci. 9, 602–604 (2006).
Shi, S.-H., Hayashi, Y., Esteban, J. A. & Malinow, R. Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell 105, 331–343 (2001).
Chowdhury, S. et al. Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron 52, 445–459 (2006).
Béïque, J.-C., Na, Y., Kuhl, D., Worley, P. F. & Huganir, R. L. Arc-dependent synapse-specific homeostatic plasticity. Proc. Natl. Acad. Sci. USA 108, 816–821 (2010).
Shepherd, J. D. et al. Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors. Neuron 52, 475–484 (2006).
Zhu, Y. et al. Rap2-JNK removes synaptic AMPA receptors during depotentiation. Neuron 46, 905–916 (2005).
Zhu, J. J., Qin, Y., Zhao, M., Van Aelst, L. & Malinow, R. Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110, 443–455 (2002).
Okuda, T., Yu, L. M. Y., Cingolani, L. A., Kemler, R. & Goda, Y. beta-Catenin regulates excitatory postsynaptic strength at hippocampal synapses. Proc. Natl. Acad. Sci. USA 104, 13479–13484 (2007).
Sanderson, J. L., Scott, J. D. & Dell’Acqua, M. L. Control of homeostatic synaptic plasticity by AKAP-anchored kinase and phosphatase regulation of Ca2+-permeable AMPA receptors. J. Neurosci. 38, 2863–2876 (2018).
Seeburg, D. P., Feliu-Mojer, M., Gaiottino, J., Pak, D. T. S. & Sheng, M. Critical role of CDK5 and polo-like kinase 2 in homeostatic synaptic plasticity during elevated activity. Neuron 58, 571–583 (2008).
Brown, T. C., Tran, I. C., Backos, D. S. & Esteban, J. A. NMDA receptor-dependent activation of the small GTPase Rab5 drives the removal of synaptic AMPA receptors during hippocampal LTD. Neuron 45, 81–94 (2005).
Fernández-Monreal, M., Brown, T. C., Royo, M. & Esteban, J. A. The balance between receptor recycling and trafficking toward lysosomes determines synaptic strength during long-term depression. J. Neurosci. 32, 13200–13205 (2012).
Brown, T. C., Correia, S. S., Petrok, C. N. & Esteban, J. A. Functional compartmentalization of endosomal trafficking for the synaptic delivery of AMPA receptors during long-term potentiation. J. Neurosci. 27, 13311–13315 (2007).
Gu, Y. et al. Differential vesicular sorting of AMPA and GABAA receptors. Proc. Natl. Acad. Sci. USA 113, E922–E931 (2016).
Mignogna, M. L. et al. The intellectual disability protein rab39b selectively regulates GluA2 trafficking to determine synaptic AMPAR composition. Nat. Commun. 6, 6504 (2015).
de Hoop, M. J. et al. The involvement of the small GTP-binding protein Rab5a in neuronal endocytosis. Neuron 13, 11–22 (1994).
Bucci, C. et al. The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway. Cell 70, 715–728 (1992).
Park, M., Penick, E. C., Edwards, J. G., Kauer, J. A. & Ehlers, M. D. Recycling endosomes supply AMPA receptors for LTP. Science 305, 1972–1975 (2004).
Petrini, E. M. et al. Endocytic trafficking and recycling maintain a pool of mobile surface AMPA receptors required for synaptic potentiation. Neuron 63, 92–105 (2009).
Steinmetz, C. C. et al. Upregulation of μ3A drives homeostatic plasticity by rerouting AMPAR into the recycling endosomal pathway. Cell Rep. 16, 2711–2722 (2016).
Chiu, S. L. et al. GRASP1 regulates synaptic plasticity and learning through endosomal recycling of AMPA receptors. Neuron 93, 1405–1419 (2017).
Ehlers, M. D. Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron 28, 511–525 (2000).
Esteves da Silva, M. et al. Positioning of AMPA receptor-containing endosomes regulates synapse architecture. Cell Rep. 13, 933–943 (2015).
Stefanko, D. P., Barrett, R. M., Ly, A. R., Reolon, G. K. & Wood, M. A. Modulation of long-term memory for object recognition via HDAC inhibition. Proc. Natl. Acad. Sci. USA 106, 9447–9452 (2009).
Guan, J. S. et al. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459, 55–60 (2009).
Hanson, J. E. et al. Histone deacetylase 2 cell autonomously suppresses excitatory and enhances inhibitory synaptic function in CA1 pyramidal neurons. J. Neurosci. 33, 5924–5929 (2013).
Koshibu, K. et al. Protein phosphatase 1 regulates the histone code for long-term memory. J. Neurosci. 29, 13079–13089 (2009).
Gao, J. et al. HDAC3 but not HDAC2 mediates visual experience-dependent radial glia proliferation in the developing Xenopus tectum. Front. Cell. Neurosci. 10, 221 (2016).
Wei, J. et al. Histone modification of ubiquitin ligase controls the loss of AMPA receptors and cognitive impairment induced by repeated stress. J. Neurosci. 36, 2119–2130 (2016).
Bhattacharya, S. et al. Histone deacetylase inhibition induces odor preference memory extension and maintains enhanced AMPA receptor expression in the rat pup model. Learn. Mem. 24, 543–551 (2017).
Asaoka, N. et al. Inhibition of histone deacetylases enhances the function of serotoninergic neurons in organotypic raphe slice cultures. Neurosci. Lett. 593, 72–77 (2015).
Aizenman, C. D. & Cline, H. T. Enhanced visual activity in vivo forms nascent synapses in the developing retinotectal projection. J. Neurophysiol. 97, 2949–2957 (2007).
Akerman, C. J. & Cline, H. T. Refining the roles of GABAergic signaling during neural circuit formation. Trends Neurosci. 30, 382–389 (2007).
Khakhalin, A. S., Koren, D., Gu, J., Xu, H. & Aizenman, C. D. Excitation and inhibition in recurrent networks mediate collision avoidance in Xenopus tadpoles. Eur. J. Neurosci. 40, 2948–2962 (2014).
Ibata, K., Sun, Q. & Turrigiano, G. G. Rapid synaptic scaling induced by changes in postsynaptic firing. Neuron 57, 819–826 (2008).
Goold, C. P. & Nicoll, R. A. Single-cell optogenetic excitation drives homeostatic synaptic depression. Neuron 68, 512–528 (2010).
Schaukowitch, K. et al. An intrinsic transcriptional program underlying synaptic scaling during activity suppression. Cell Rep. 18, 1512–1526 (2017).
Zhong, P., Liu, W. H., Gu, Z. L. & Yan, Z. Serotonin facilitates long-term depression induction in prefrontal cortex via p38 MAPK/Rab5-mediated enhancement of AMPA receptor internalization. J. Physiol. 586, 4465–4479 (2008).
Snigdha, S. et al. H3K9me3 inhibition improves memory, promotes spine formation, and increases BDNF levels in the aged hippocampus. J. Neurosci. 36, 3611–3622 (2016).
Kopp, C., Longordo, F., Nicholson, J. R. & Lüthi, A. Insufficient sleep reversibly alters bidirectional synaptic plasticity and NMDA receptor function. J. Neurosci. 26, 12456–12465 (2006).
Tao, H. W. & Poo, M. -m Activity-dependent matching of excitatory and inhibitory inputs during refinement of visual receptive fields. Neuron 45, 829–836 (2005).
Niell, C. M. & Smith, S. J. Functional imaging reveals rapid development of visual response properties in the Zebrafish tectum. Neuron 45, 941–951 (2005).
Zhou, Q., Tao, H. W. & Poo, M. -m Reversal and stabilization of synaptic modifications in a developing visual system. Science 300, 1953–1957 (2003).
Whitt, J. L., Petrus, E. & Lee, H. K. Experience-dependent homeostatic synaptic plasticity in neocortex. Neuropharmacology 78, 45–54 (2014).
O’Brien, R. J. et al. Activity-dependent modulation of synaptic AMPA receptor accumulation. Neuron 21, 1067–1078 (1998).
Turrigiano, G. G., Leslie, K. R., Desai, N. S., Rutherford, L. C. & Nelson, S. B. Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature 391, 892–896 (1998).
Huang, L. C., Mckeown, C. R., He, H. Y., Ta, A. C. & Cline, H. T. BRCA1 and ELK-1 regulate neural progenitor cell fate in the optic tectum in response to visual experience in Xenopus laevis tadpoles. Proc. Natl. Acad. Sci. USA 121, e2316542121 (2024).
Ta, A. C. et al. Temporal and spatial transcriptomic dynamics across brain development in Xenopus laevis tadpoles. G3 12, kab387 (2022).
Goel, A. et al. Cross-modal regulation of synaptic AMPA receptors in primary sensory cortices by visual experience. Nat. Neurosci. 9, 1001–1003 (2006).
Zhang, M. et al. Functional elimination of excitatory feedforward inputs underlies developmental refinement of visual receptive fields in Zebrafish. J. Neurosci. 31, 5460–5469 (2011).
Rohrbough, J. & Spitzer, N. C. Ca2+-permeable AMPA receptors and spontaneous presynaptic transmitter release at developing excitatory spinal synapses. J. Neurosci. 19, 8528–8541 (1999).
Thiagarajan, T. C., Piedras-Renteria, E. S. & Tsien, R. W. α- and βCaMKII: inverse regulation by neuronal activity and opposing effects on synaptic strength. Neuron 36, 1103–1114 (2002).
Wierenga, C. J., Ibata, K. & Turrigiano, G. G. Postsynaptic expression of homeostatic plasticity at neocortical synapses. J. Neurosci. 25, 2895–2905 (2005).
Lanté, F., Toledo-Salas, J.-C., Ondrejcak, T., Rowan, M. J. & Ulrich, D. Removal of synaptic Ca2+-permeable AMPA receptors during sleep. J. Neurosci. 31, 3953–3961 (2011).
Makino, H. & Malinow, R. AMPA receptor incorporation into synapses during LTP: The role of lateral movement and exocytosis. Neuron 64, 381–390 (2009).
He, K. W., Petrus, E., Gammon, N. & Lee, H. K. Distinct sensory requirements for unimodal and cross-modal homeostatic synaptic plasticity. J. Neurosci. 32, 8469–8474 (2012).
Hou, Q. M. et al. MicroRNA miR124 is required for the expression of homeostatic synaptic plasticity. Nat. Commun. 6, 10045 (2015).
Heo, H. Y., Kim, K. S. & Seol, W. Coordinate regulation of neurite outgrowth by LRRK2 and its interactor, Rab5. Exp. Neurobiol. 19, 97–105 (2010).
Szíber, Z. et al. Ras and Rab interactor 1 controls neuronal plasticity by coordinating dendritic filopodial motility and AMPA receptor turnover. Mol. Biol. Cell 28, 285–295 (2017).
Mori, Y., Matsui, T. & Fukuda, M. Rabex-5 protein regulates dendritic localization of small GTPase Rab17 and neurite morphogenesis in hippocampal neurons. J. Biol. Chem. 288, 9835–9847 (2013).
Villarroel-Campos, D., Bronfman, F. C. & Gonzalez-Billault, C. Rab GTPase signaling in neurite outgrowth and axon specification. Cytoskeleton 73, 498–507 (2016).
Gainey, M. A., Hurvitz-Wolff, J. R., Lambo, M. E. & Turrigiano, G. G. Synaptic scaling requires the GluR2 subunit of the AMPA receptor. J. Neurosci. 29, 6479–6489 (2009).
Kumar, S. S., Bacci, A., Kharazia, V. & Huguenard, J. R. A developmental switch of AMPA receptor subunits in neocortical pyramidal neurons. J. Neurosci. 22, 3005–3015 (2002).
Lawrence, J. J. & Trussell, L. O. Long-term specification of AMPA receptor properties after synapse formation. J. Neurosci. 20, 4864–4870 (2000).
Zhou, Z. et al. The C-terminal tails of endogenous GluA1 and GluA2 differentially contribute to hippocampal synaptic plasticity and learning. Nat. Neurosci. 21, 50–62 (2017).
Lin, D. T. & Huganir, R. L. PICK1 and phosphorylation of the glutamate receptor 2 (GluR2) AMPA receptor subunit regulates GluR2 recycling after NMDA receptor-induced internalization. J. Neurosci. 27, 13903–13908 (2007).
Passafaro, M., Piëch, V. & Sheng, M. Subunit-specific temporal and spatial patterns of AMPA receptor exocytosis in hippocampal neurons. Nat. Neurosci. 4, 917–926 (2001).
Gromova, K. V. et al. The kinesin Kif21b binds myosin va and mediates changes in actin dynamics underlying homeostatic synaptic downscaling. Cell Rep. 42, 112743 (2023).
Hou, Q. M., Gilbert, J. & Man, H. Y. Homeostatic regulation of AMPA receptor trafficking and degradation by light-controlled single-synaptic activation. Neuron 72, 806–818 (2011).
Matsuda, S. et al. Stargazin regulates AMPA receptor trafficking through adaptor protein complexes during long-term depression. Nat. Commun. 4, 2759 (2013).
Peng, Y. R. et al. Coordinated changes in dendritic arborization and synaptic strength during neural circuit development. Neuron 61, 71–84 (2009).
Hsieh, H. et al. AMPAR removal underlies Aβ-induced synaptic depression and dendritic spine loss. Neuron 52, 831–843 (2006).
Akhtar, M. W. et al. Histone deacetylases 1 and 2 form a developmental switch that controls excitatory synapse maturation and function. J. Neurosci. 29, 8288–8297 (2009).
Jayanthi, S. et al. Methamphetamine downregulates striatal glutamate receptors via diverse epigenetic mechanisms. Biol. Psychiatry 76, 47–56 (2014).
Authement, M. E. et al. Histone deacetylase inhibition rescues maternal deprivation-induced GABAergic metaplasticity through restoration of AKAP signaling. Neuron 86, 1240–1252 (2015).
Nieuwkoop, P. & Faber, J. Normal Table of Xenopus laevis (Daudin) (Garland Publishing Inc, 1994).
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This work was supported by the Interdisciplinary Research Project of Hangzhou Normal University (2024JCXK01) and the National Natural Science Foundation of China (NSFC 31871041).
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L.Z. and W.S. designed the experiment. L.Z., X.D., W.H., Y.L., Y.W., Q.L., X.W., L.H., and W.S. performed the experiments. L.Z., X.D. and W.S. analyzed the data. W.S. wrote the manuscript.
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Zheng, L., Duan, X., Huang, W. et al. Prolonged visual experience accelerates developmental synaptic downscaling via epigenetic regulation and Rab5c mediated AMPA receptor trafficking. Commun Biol (2026). https://doi.org/10.1038/s42003-025-09507-5
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DOI: https://doi.org/10.1038/s42003-025-09507-5
