Zheng L et al. (2026), Prolonged visual experience accelerates develop...

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Commun Biol 2026 Jan 09;91:230. doi: 10.1038/s42003-025-09507-5.

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Prolonged visual experience accelerates developmental synaptic downscaling via epigenetic regulation and Rab5c mediated AMPA receptor trafficking.

Zheng L, Duan X, Huang W, Luo Y, Wu Y, Lin Q, Wu X, Han L, Shen W.

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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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Species referenced: Xenopus laevis

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	graphical abstract
	Fig. 1. Prolonged light exposure reduces mEPSC amplitudes in tectal neurons.a Schematic representation of light exposure conditions: control (12LE), long-day exposure (20LE), and short-day exposure (4LE). b–d Representative mEPSCs traces from tectal neurons exposed to 4LE, 12LE, and 20LE at 2 dpl (b), 5 dpl (c), and 8 dpl (d). Scale bar: 20 pA, 2 s. e Quantitative analysis shows that mEPSCs amplitudes decrease in 20LE tadpoles compared to 12LE tadpoles at 2, 5, and 8 dpl. 2 dpl: n = 24, 19, 17; 5 dpl: n = 19, 16, 21; 8 dpl: n = 12, 14, 9 for 4LE, 12LE, and 20LE. f No significant changes were observed in inter-event intervals (IEIs) or mEPSC frequencies for 20LE-treated neurons compared to 12LE across all time points. p < 0.05, *p < 0.01 (Kolmogorov–Smirnov test or ANOVA with Newman–Keuls post hoc test).
	Fig. 2. Long-day exposure decreases excitatory synaptic inputs.a Representative trace of visually evoked excitatory compound synaptic currents (eCSCs) in response to full-field light off visual stimuli (luminance: 20 cd m-2) in 4LE, 12LE, and 20LE-treated neurons at 2 dpl. Scale bar: 30 pA, 2 s. b, c Quantitative analyses showing that both the amplitude (b) and integrated current (c) of eCSCs were significantly lower in the 20LE-treated neurons compared to 12LE. n = 19, 17, 19 for 4LE, 12LE, and 20LE. d Representative electrophysiological recordings of EPSCs in response to paired-pulse stimuli (intervals of 20, 50, and 100 ms) in neurons from 4LE, 12LE, and 20LE groups at 2 dpl. Stimulus artifacts were removed for clarity. Scale bar: 50 pA, 50 ms. e, f No significant differences in paired-pulse ratio (EPSC2/EPSC1) were observed at 2 dpl (e) or 5 dpl (f) among the three groups. 2 dpl: n = 11, 14, 10; 5 dpl: n = 4, 5, 8 for 4LE, 12LE, and 20LE. *p < 0.05.
	Fig. 3. Long-day exposure increases intrinsic neuronal excitability.a Representative traces of action potentials induced by current injection in neurons from 4LE, 12LE, and 20LE groups. Scale bar: 40 mV, 40 ms. b–d Summary data showing that 20LE, but not 4LE, increases intrinsic neuronal excitability compared to 12LE neurons at 2 dpl (b), 5 dpl (c), and 8 dpl (d). 2 dpl: n = 13, 17, 18; 5 dpl: n = 13, 12, 10; 8 dpl: n = 11, 9, 6 for 4LE, 12LE, and 20LE. MP: membrane potential. e–g Membrane capacitance (Cm), input resistance (Rin), and resting membrane potential (Vm) were not significantly altered among 4LE, 12LE, and 20LE-treated neurons at 2 dpl. 4LE/12LE/20LE: n = 18, 22, 15. p < 0.05, *p < 0.01.
	Fig. 4. Transcriptomic changes induced by altered light exposure.a Heatmap showing gene expression in tectal neurons exposed to 4LE, 12LE, and 20LE at 2 dpl and 5 dpl. b, c Venn diagrams showing the intersections between upregulated and downregulated genes in the tectum under 20LE, 4LE, and 12LE conditions at 2 dpl (b) and 5 dpl (c). d, e qRT-PCR analysis showing changes in gria1.L and gria2.S expression levels at 2 dpl (d) and 5 dpl (e), 2 dpl: n = 3, 3; 5 dpl: n = 5, 5 for gria1.L and gria2.S. *p < 0.05.
	Fig. 5. Long-day exposure changes the expression levels of GluA1, GluA2 and Rab5c.a Representative Western blots showing GluA1, GluA2, and Rab5c protein levels in tadpoles treated with 4LE, 12LE, and 20LE at 2, 5, and 8 dpl. b Quantitative analysis indicates a significant decrease in GluA1 and GluA2 expression in 20LE-treated tadpoles compared to 12LE at 5 and 8 dpl, whereas Rab5c is transiently upregulated at 2 dpl in 20LE. GluA1, GluA2 and Rab5c: n = 3–7 per group at each time point (two-way ANOVA with post hoc Fisher’s LSD test). c Representative Western blots of GluA1, GluA2, PSD95, HDAC2 and Rab5c in synaptosomal, cytosolic and total input fractions. d, e Synaptosomal analysis shows reduced GluA2 and increased Rab5c levels in 20LE tadpoles compared to 12LE. GluA1: n = 4, 4, 4; GluA2: n = 4, 4, 4; Rab5c: n = 5, 6, 5 for 4LE, 12LE, and 20LE. p < 0.05; *p < 0.01 (one-way ANOVA with post hoc Dunnett’s test).
	Fig. 6. Prolonged light exposure alters neuronal architecture.a, b Illustrative examples of complete dendritic arbor reconstructions from time-lapse imaging of control (Ctrl-GFP), Rab5c-overexpressing (Rab5c-GFP), and Rab5c knockdown (Rab5c-MO) tectal neurons in 12LE and 20LE tadpoles. Upper panels: raw confocal microscopy images; lower panels: 3D reconstructions using Imaris. Arrowheads indicate axons. c–e Quantitative analysis of total dendritic branch length (TDBL), branch tip number (TBTN), and dendritic area. 12LE: n = 7, 7, 8; 20LE: n = 8, 11, 7 for Ctrl-GFP, Rab5c-GFP and Rab5c-MO + Ctrl-GFP. p < 0.05, p < 0.01, **p < 0.001 (two-way ANOVA with post hoc Tukey’s HSD test).
	Fig. 7. Rab5c mediates AMPA receptor trafficking during synaptic scaling.a Representative mEPSCs traces from tadpoles under the following treatment groups: 12LE (2 dpl) + 12LE (2 dpl): raised in 12LE for 4 days; 20LE (2 dpl) + 20LE (2 dpl): raised in 20LE for 4 days; 20LE (2 dpl) + 12LE (2 dpl): raised in 20LE for 2 days followed by 12LE for 2 days; 20LE (2 dpl) + Rab5c-MO (2 dpl): raised in 20LE for 2 days followed by Rab5c-MO for 2 days; 20LE (2 dpl) + Rab5c-GFP (2 dpl): raised in 20LE for 2 days followed by Rab5c-GFP for 2 days; 20LE (2 dpl) + Ctrl-MO (5 dpl): raised in 20LE for 2 days followed by Ctrl-MO for 5 days; 20LE (2 dpl) + Rab5c-MO (5 dpl): raised in 20LE for 2 days followed by Rab5c-MO for 5 days. b, c Summary of mEPSC amplitude changes. n = 16, 21, 23, 13, 27 (b, left to right); n = 10, 12 for Ctrl-MO and Rab5c-MO (c). d Representative traces for visually evoked eCSCs in Ctrl, Rab5c-GFP, and Rab5c-MO neurons at 5 dpl. Scale bar: 30 pA, 2 s. e, f Summary data showing that the amplitude (e) and integrated current (f) of eCSCs are restored in 20LE + Rab5c-MO compared to 20LE + Ctrl-GFP neurons. n = 11, 14, 11 for Ctrl, Rab5c-GFP and Rab5c-MO. g–i Western blots show increased GluA1 and GluA2 protein levels of synaptosomal fractions in 20LE + 12LE brains compared to 20LE + 20LE. GluA1 and GluA2: n = 4, 5 for 20LE + 20LE, and 20LE + 12LE. p < 0.05, *p < 0.01.
	Fig. 8. Long-day exposure increases histone acetylation.a Western blot analysis shows acetylation levels of H3K9Ac, H2BK5Ac and H4K8Ac in 4LE, 12LE, and 20LE groups at 2, 5, and 8 dpl. b–d Summary data reveal significantly elevated histone acetylation in 20LE brain compared to 12LE. 2 dpl/5 dpl/8 dpl: H3K9Ac: n = 9/6/7, 9/6/7, 9/6/7; H2BK5Ac: n = 8/4/4, 8/4/4, 8/4/4; H4K8Ac: n = 9/6/6, 9/6/6, 9/6/6 for 4LE, 12LE, and 20LE. p < 0.05; p < 0.01; **p < 0.001 (two-way ANOVA with post hoc Fisher’s LSD test).
	Fig. 9. Histone deacetylases regulate mEPSC amplitude, intrinsic excitability and AMPAR expression.a Representative mEPSC traces from Ctrl-MO, HDAC2-MO, and HDAC3-MO neurons at 2 dpl. Scale bar: 20 pA, 20 s. b Quantification shows that HDAC2-MO and HDAC3-MO reduce mEPSC amplitudes. n = 6, 8, 11 for Ctrl-MO, HDAC2-MO, and HDAC3-MO. c Representative mEPSC traces from Ctrl-GFP, HDAC1-GFP, HDAC2-GFP and HDAC3-GFP neurons in 20LE tadpoles at 2 dpl. Scale bar: 20 pA, 20 s. d Summary data showing that Ctrl-GFP, HDAC1-GFP, HDAC2-GFP, and HDAC3-GFP increase mEPSC amplitudes. n = 23, 17, 14, 16 for Ctrl-GFP, HDAC1-GFP, HDAC2-GFP, and HDAC3-GFP. e Representative traces of current injection-induced spikes in control and TSA-treated neurons. n = 10, 9 for Ctrl and TSA. Scale bar: 40 mV, 40 ms. f Summary data showing that TSA treatment increases intrinsic excitability compared to control neurons. g–i Western blot analysis showing that TSA treatment downregulates GluA1 and GluA2 protein expression. GluA1: n = 7, 7; GluA2: n = 4, 4 for Ctrl and TSA. j–m Western blot analysis showing that HDAC2-MO decreases GluA2 expression, whereas HDAC3-MO downregulates GluA1 and GluA2 but increases Rab5c expression. Rab5c and GluA2: n = 4 per group; GluA1: n = 3 per group. n–q Western blot analysis showing that Rab5c-MO increases H3K9Ac, H2BK5Ac, and H4K8Ac levels. H3K9Ac: n = 8 per group; H2BK5Ac: n = 3 per group; H4K8Ac: n = 4 per group. p < 0.05; p < 0.01; **p < 0.001.

	graphical abstract
	Fig. 1. Prolonged light exposure reduces mEPSC amplitudes in tectal neurons.a Schematic representation of light exposure conditions: control (12LE), long-day exposure (20LE), and short-day exposure (4LE). b–d Representative mEPSCs traces from tectal neurons exposed to 4LE, 12LE, and 20LE at 2 dpl (b), 5 dpl (c), and 8 dpl (d). Scale bar: 20 pA, 2 s. e Quantitative analysis shows that mEPSCs amplitudes decrease in 20LE tadpoles compared to 12LE tadpoles at 2, 5, and 8 dpl. 2 dpl: n = 24, 19, 17; 5 dpl: n = 19, 16, 21; 8 dpl: n = 12, 14, 9 for 4LE, 12LE, and 20LE. f No significant changes were observed in inter-event intervals (IEIs) or mEPSC frequencies for 20LE-treated neurons compared to 12LE across all time points. p < 0.05, *p < 0.01 (Kolmogorov–Smirnov test or ANOVA with Newman–Keuls post hoc test).
	Fig. 2. Long-day exposure decreases excitatory synaptic inputs.a Representative trace of visually evoked excitatory compound synaptic currents (eCSCs) in response to full-field light off visual stimuli (luminance: 20 cd m-2) in 4LE, 12LE, and 20LE-treated neurons at 2 dpl. Scale bar: 30 pA, 2 s. b, c Quantitative analyses showing that both the amplitude (b) and integrated current (c) of eCSCs were significantly lower in the 20LE-treated neurons compared to 12LE. n = 19, 17, 19 for 4LE, 12LE, and 20LE. d Representative electrophysiological recordings of EPSCs in response to paired-pulse stimuli (intervals of 20, 50, and 100 ms) in neurons from 4LE, 12LE, and 20LE groups at 2 dpl. Stimulus artifacts were removed for clarity. Scale bar: 50 pA, 50 ms. e, f No significant differences in paired-pulse ratio (EPSC2/EPSC1) were observed at 2 dpl (e) or 5 dpl (f) among the three groups. 2 dpl: n = 11, 14, 10; 5 dpl: n = 4, 5, 8 for 4LE, 12LE, and 20LE. *p < 0.05.
	Fig. 3. Long-day exposure increases intrinsic neuronal excitability.a Representative traces of action potentials induced by current injection in neurons from 4LE, 12LE, and 20LE groups. Scale bar: 40 mV, 40 ms. b–d Summary data showing that 20LE, but not 4LE, increases intrinsic neuronal excitability compared to 12LE neurons at 2 dpl (b), 5 dpl (c), and 8 dpl (d). 2 dpl: n = 13, 17, 18; 5 dpl: n = 13, 12, 10; 8 dpl: n = 11, 9, 6 for 4LE, 12LE, and 20LE. MP: membrane potential. e–g Membrane capacitance (Cm), input resistance (Rin), and resting membrane potential (Vm) were not significantly altered among 4LE, 12LE, and 20LE-treated neurons at 2 dpl. 4LE/12LE/20LE: n = 18, 22, 15. p < 0.05, *p < 0.01.
	Fig. 4. Transcriptomic changes induced by altered light exposure.a Heatmap showing gene expression in tectal neurons exposed to 4LE, 12LE, and 20LE at 2 dpl and 5 dpl. b, c Venn diagrams showing the intersections between upregulated and downregulated genes in the tectum under 20LE, 4LE, and 12LE conditions at 2 dpl (b) and 5 dpl (c). d, e qRT-PCR analysis showing changes in gria1.L and gria2.S expression levels at 2 dpl (d) and 5 dpl (e), 2 dpl: n = 3, 3; 5 dpl: n = 5, 5 for gria1.L and gria2.S. *p < 0.05.
	Fig. 5. Long-day exposure changes the expression levels of GluA1, GluA2 and Rab5c.a Representative Western blots showing GluA1, GluA2, and Rab5c protein levels in tadpoles treated with 4LE, 12LE, and 20LE at 2, 5, and 8 dpl. b Quantitative analysis indicates a significant decrease in GluA1 and GluA2 expression in 20LE-treated tadpoles compared to 12LE at 5 and 8 dpl, whereas Rab5c is transiently upregulated at 2 dpl in 20LE. GluA1, GluA2 and Rab5c: n = 3–7 per group at each time point (two-way ANOVA with post hoc Fisher’s LSD test). c Representative Western blots of GluA1, GluA2, PSD95, HDAC2 and Rab5c in synaptosomal, cytosolic and total input fractions. d, e Synaptosomal analysis shows reduced GluA2 and increased Rab5c levels in 20LE tadpoles compared to 12LE. GluA1: n = 4, 4, 4; GluA2: n = 4, 4, 4; Rab5c: n = 5, 6, 5 for 4LE, 12LE, and 20LE. p < 0.05; *p < 0.01 (one-way ANOVA with post hoc Dunnett’s test).
	Fig. 6. Prolonged light exposure alters neuronal architecture.a, b Illustrative examples of complete dendritic arbor reconstructions from time-lapse imaging of control (Ctrl-GFP), Rab5c-overexpressing (Rab5c-GFP), and Rab5c knockdown (Rab5c-MO) tectal neurons in 12LE and 20LE tadpoles. Upper panels: raw confocal microscopy images; lower panels: 3D reconstructions using Imaris. Arrowheads indicate axons. c–e Quantitative analysis of total dendritic branch length (TDBL), branch tip number (TBTN), and dendritic area. 12LE: n = 7, 7, 8; 20LE: n = 8, 11, 7 for Ctrl-GFP, Rab5c-GFP and Rab5c-MO + Ctrl-GFP. p < 0.05, p < 0.01, **p < 0.001 (two-way ANOVA with post hoc Tukey’s HSD test).
	Fig. 7. Rab5c mediates AMPA receptor trafficking during synaptic scaling.a Representative mEPSCs traces from tadpoles under the following treatment groups: 12LE (2 dpl) + 12LE (2 dpl): raised in 12LE for 4 days; 20LE (2 dpl) + 20LE (2 dpl): raised in 20LE for 4 days; 20LE (2 dpl) + 12LE (2 dpl): raised in 20LE for 2 days followed by 12LE for 2 days; 20LE (2 dpl) + Rab5c-MO (2 dpl): raised in 20LE for 2 days followed by Rab5c-MO for 2 days; 20LE (2 dpl) + Rab5c-GFP (2 dpl): raised in 20LE for 2 days followed by Rab5c-GFP for 2 days; 20LE (2 dpl) + Ctrl-MO (5 dpl): raised in 20LE for 2 days followed by Ctrl-MO for 5 days; 20LE (2 dpl) + Rab5c-MO (5 dpl): raised in 20LE for 2 days followed by Rab5c-MO for 5 days. b, c Summary of mEPSC amplitude changes. n = 16, 21, 23, 13, 27 (b, left to right); n = 10, 12 for Ctrl-MO and Rab5c-MO (c). d Representative traces for visually evoked eCSCs in Ctrl, Rab5c-GFP, and Rab5c-MO neurons at 5 dpl. Scale bar: 30 pA, 2 s. e, f Summary data showing that the amplitude (e) and integrated current (f) of eCSCs are restored in 20LE + Rab5c-MO compared to 20LE + Ctrl-GFP neurons. n = 11, 14, 11 for Ctrl, Rab5c-GFP and Rab5c-MO. g–i Western blots show increased GluA1 and GluA2 protein levels of synaptosomal fractions in 20LE + 12LE brains compared to 20LE + 20LE. GluA1 and GluA2: n = 4, 5 for 20LE + 20LE, and 20LE + 12LE. p < 0.05, *p < 0.01.
	Fig. 8. Long-day exposure increases histone acetylation.a Western blot analysis shows acetylation levels of H3K9Ac, H2BK5Ac and H4K8Ac in 4LE, 12LE, and 20LE groups at 2, 5, and 8 dpl. b–d Summary data reveal significantly elevated histone acetylation in 20LE brain compared to 12LE. 2 dpl/5 dpl/8 dpl: H3K9Ac: n = 9/6/7, 9/6/7, 9/6/7; H2BK5Ac: n = 8/4/4, 8/4/4, 8/4/4; H4K8Ac: n = 9/6/6, 9/6/6, 9/6/6 for 4LE, 12LE, and 20LE. p < 0.05; p < 0.01; **p < 0.001 (two-way ANOVA with post hoc Fisher’s LSD test).
	Fig. 9. Histone deacetylases regulate mEPSC amplitude, intrinsic excitability and AMPAR expression.a Representative mEPSC traces from Ctrl-MO, HDAC2-MO, and HDAC3-MO neurons at 2 dpl. Scale bar: 20 pA, 20 s. b Quantification shows that HDAC2-MO and HDAC3-MO reduce mEPSC amplitudes. n = 6, 8, 11 for Ctrl-MO, HDAC2-MO, and HDAC3-MO. c Representative mEPSC traces from Ctrl-GFP, HDAC1-GFP, HDAC2-GFP and HDAC3-GFP neurons in 20LE tadpoles at 2 dpl. Scale bar: 20 pA, 20 s. d Summary data showing that Ctrl-GFP, HDAC1-GFP, HDAC2-GFP, and HDAC3-GFP increase mEPSC amplitudes. n = 23, 17, 14, 16 for Ctrl-GFP, HDAC1-GFP, HDAC2-GFP, and HDAC3-GFP. e Representative traces of current injection-induced spikes in control and TSA-treated neurons. n = 10, 9 for Ctrl and TSA. Scale bar: 40 mV, 40 ms. f Summary data showing that TSA treatment increases intrinsic excitability compared to control neurons. g–i Western blot analysis showing that TSA treatment downregulates GluA1 and GluA2 protein expression. GluA1: n = 7, 7; GluA2: n = 4, 4 for Ctrl and TSA. j–m Western blot analysis showing that HDAC2-MO decreases GluA2 expression, whereas HDAC3-MO downregulates GluA1 and GluA2 but increases Rab5c expression. Rab5c and GluA2: n = 4 per group; GluA1: n = 3 per group. n–q Western blot analysis showing that Rab5c-MO increases H3K9Ac, H2BK5Ac, and H4K8Ac levels. H3K9Ac: n = 8 per group; H2BK5Ac: n = 3 per group; H4K8Ac: n = 4 per group. p < 0.05; p < 0.01; **p < 0.001.