Ube3a is required for experience-dependent maturation of the neocortex - PubMed (original) (raw)
Ube3a is required for experience-dependent maturation of the neocortex
Koji Yashiro et al. Nat Neurosci. 2009 Jun.
Abstract
Experience-dependent maturation of neocortical circuits is required for normal sensory and cognitive abilities, which are distorted in neurodevelopmental disorders. We tested whether experience-dependent neocortical modifications require Ube3a, an E3 ubiquitin ligase whose dysregulation has been implicated in autism and Angelman syndrome. Using visual cortex as a model, we found that experience-dependent maturation of excitatory cortical circuits was severely impaired in Angelman syndrome model mice deficient in Ube3a. This developmental defect was associated with profound impairments in neocortical plasticity. Normal plasticity was preserved under conditions of sensory deprivation, but was rapidly lost by sensory experiences. The loss of neocortical plasticity is reversible, as late-onset visual deprivation restored normal synaptic plasticity. Furthermore, Ube3a-deficient mice lacked ocular dominance plasticity in vivo when challenged with monocular deprivation. We conclude that Ube3a is necessary for maintaining plasticity during experience-dependent neocortical development and suggest that the loss of neocortical plasticity contributes to deficits associated with Angelman syndrome.
Conflict of interest statement
Competing interests statement: The authors declare no competing financial interests.
Figures
Figure 1. Reduced functional maturation of neocortical synapses in AS mice
a, Immunoblot (IB) analysis of Ube3a in tissue from young (P26) WT, Ube3am+/p-, and Ube3am−/p+ mice. b, Immunohistochemical analysis of Ube3a expression in the visual cortex from young (P24) WT and Ube3am−/p+ mice. Strong Ube3a immunoreactivity was observed in layer 2/3 (L2/3) neurons of WT mice. NeuN antibody stains cell bodies of neurons. Scale bars, 50 μm. c, Representative traces of mEPSCs recorded in L2/3 pyramidal neurons from WT (upper) or Ube3am−/p+ (lower) mice at ∼P10, ∼P25, and ∼P100. Scale bars, 0.2 sec, 20 pA. d, Average mEPSC amplitude as a function of postnatal age in WT (P10, n = 11 cells; P25, n =11 cells; P100, n =12 cells) and Ube3am−/p+ mice (P10, n =11 cells; P25, n =12 cells; P100, n =12 cells). e, Average mEPSC frequency as a function of postnatal age in WT and Ube3am−/p+. * p < 0.05, ** p < 0.005. Error bars in this and all subsequent figures represent s.e.m.
Figure 2. Sensory experience augments excitatory synaptic connections in the neocortex of WT mice, but not AS mice
a, Schematic for the rearing conditions. Normally-reared (NR) animals were maintained in a 12 h consecutive dark:light cycle, and dark-reared (DR) animals were kept in complete darkness from ∼P10. b, Representative traces of mEPSCs recorded in layer 2/3 pyramidal neurons in young WT (left) or Ube3am−/p+ (right) mice reared in complete darkness (DR) or normally (NR). Scale bar: 0.2 sec, 20 pA. c, Dark-rearing does not affect mEPSC amplitude in WT (DR, n = 12 cells; NR, n = 11 cells) or Ube3am−/p+ mice (DR, n = 14 cells; NR, n = 12 cells). d, Dark-rearing significantly reduces mEPSC frequency in WT mice, but does not affect mEPSC frequency in Ube3am−/p+ mice. e, Representative images of basal dendrites of layer 2/3 pyramidal neurons visualized with Golgi staining. Scale bar, 10 μm. f, Average density of dendritic spines in DR (WT, n = 25 cells; Ube3am−/p+, n = 25 cells) and in NR (WT, n = 33 cells; Ube3am−/p+, n = 32 cells). *** p < 0.0005.
Figure 3. Synaptic plasticity is impaired bidirectionally in the neocortex of AS mice
a, Schematic diagram of stimulating (S) and recording (R) configuration. b, Baseline synaptic responses of WT (open circle) and Ube3am−/p+ (closed triangle) mice were measured before and after application of conditioning stimuli to the layer 4 (L4) to L2/3 pathway of the visual cortex. Top traces are representative averaged traces of 15 min baseline (1), 30-45 min period after LTD induction (2), and their overlays (1, 2). Scale bars: 10 ms, 1 mV. The bottom graph describes average change in field EPSP (% fEPSP) upon delivery of a 1 Hz stimulus (indicated by the bar). Whereas 1 Hz stimulation for 15 min induced LTD in young WT mice, it did not change fEPSP amplitudes in Ube3am−/p+ mice (Percentage field excitatory postsynaptic potential (fEPSP): WT, n = 13 slices; Ube3am−/p+, n = 7 slices; p < 0.04). c, Same as b, except that a stimulus consisting of three 40 Hz trains was delivered (indicated by an arrow). While this stimulation induced LTP in WT mice, it did not alter fEPSP amplitudes in Ube3am−/p+ mice (WT, n = 12 slices; Ube3am−/p+, n = 10 slices; p < 0.02). d, Same as c, except that the stimulus consisted of two 100 Hz trains (indicated by an arrow). This stimulation induced LTP in both genotypes (WT, n = 12 slices; Ube3am−/p+, n = 10 slices; p = 0.59). e, Frequency-response functions derived from visual cortex of WT and Ube3am−/p+ mice. Data points represent percent changes in fEPSP 30-45 min after the delivery of conditioning stimuli. The data points for 0.033 Hz are inferred from baseline stimulation delivered once every 30 sec, which induced no obvious synaptic modifications.
Figure 4. Sensory experience eliminates neocortical plasticity in AS mice
a, Schematic of the recording configuration. b, Schematic for the dark-rearing condition. c, Representative waveforms and averaged data demonstrating that the level of LTP induced with 40 Hz stimulation is comparable between WT (n = 18) and Ube3am−/p+ (n = 18) mice reared in complete darkness (p = 0.91). Scale bars: 10 ms, 0.5 mV. d, The level of LTD is also comparable between WT and Ube3am−/p+ dark-reared mice (WT, n = 16 slices; Ube3am−/p+, n = 17 slices; p = 0.69). e, Schematic showing the schedule for exposing dark-reared mice to light. f, One day of normal-rearing following dark-rearing attenuates LTD in visual cortical slices from Ube3am−/p+ mice (WT, n = 19; Ube3am−/p+, n = 15; p = 0.08). g, Four days of normal-rearing following dark-rearing completely suppresses LTD in visual cortical slices from Ube3am−/p+ mice (WT, n = 9; Ube3am−/p+, n = 6; p < 0.01). h, Visual experience dampens LTD in the visual cortex of Ube3am−/p+ mice. Data represent means ± SEM of the percent reduction in fEPSP 30-45 min after the delivery of conditioning stimuli measured in normally-reared (NR), dark-reared (DR), and dark-then-light exposed for 1 or 4 days (DR+1L, DR+4L) mice.
Figure 5. Late-onset visual deprivation restores synaptic plasticity in AS mice
a, Schematic of the recording configuration. b, Schematic for the late-onset visual deprivation (LOVD) rearing condition. c, Averaged data demonstrating that LTD is abolished in normally reared (NR) WT mice at ∼P40, while LTD of a similar magnitude was induced after LOVD in WT and Ube3am−/p+ mice (% fEPSP: NR WT, n = 10 slices; LOVD WT, n = 10 slices; LOVD Ube3am−/p+, n = 11 slices; p < 0.05, NR WT is significantly different from both LOVD WT and LOVD Ube3am−/p+, one-way ANOVA followed by Tukey). d, Bar graph of data shown in c.
Figure 6. Critical period ocular dominance plasticity is absent in AS mice
a, Schedule of the surgery and recording. b, Changes in the ratio of contralateral to ipsilateral eye responses (C/I ratio) in MD (n = 13 mice) and non-deprived control WT mice (n = 14 mice) from P27 (Day 0) to P30 (Day 3). After 3 days of MD, the C/I ratio was significantly reduced (paired t-test p < 0.01), whereas this reduction was not observed in age-matched non-deprived controls (paired t-test p = 0.14). c, C/I ratios in Ube3am−/p+ mice (MD = 11 mice, control = 9 mice). MD did not affect the C/I ratio (paired t-test p = 0.52). C/I ratio was stable for 3 days in age-matched non-deprived controls (paired t-test p = 0.53). d, MD-induced changes in contralateral but not ipsilateral VEPs in WT mice. Top traces are representative waveforms of VEPs recorded in WT mice. Scale bars: 50 μV, 50 msec. The bottom graph describes comparisons of VEP amplitudes between control and monocularly deprived WT mice (* p < 0.05). e, Same as d except that experiments were conducted in Ube3am−/p+ mice.
Similar articles
- Genomic imprinting of experience-dependent cortical plasticity by the ubiquitin ligase gene Ube3a.
Sato M, Stryker MP. Sato M, et al. Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5611-6. doi: 10.1073/pnas.1001281107. Epub 2010 Mar 8. Proc Natl Acad Sci U S A. 2010. PMID: 20212164 Free PMC article. - Maternal Loss of Ube3a Impairs Experience-Driven Dendritic Spine Maintenance in the Developing Visual Cortex.
Kim H, Kunz PA, Mooney R, Philpot BD, Smith SL. Kim H, et al. J Neurosci. 2016 Apr 27;36(17):4888-94. doi: 10.1523/JNEUROSCI.4204-15.2016. J Neurosci. 2016. PMID: 27122043 Free PMC article. - Reversible blockade of experience-dependent plasticity by calcineurin in mouse visual cortex.
Yang Y, Fischer QS, Zhang Y, Baumgärtel K, Mansuy IM, Daw NW. Yang Y, et al. Nat Neurosci. 2005 Jun;8(6):791-6. doi: 10.1038/nn1464. Epub 2005 May 8. Nat Neurosci. 2005. PMID: 15880107 - Towards an understanding of Angelman syndrome in mice studies.
Yang X. Yang X. J Neurosci Res. 2020 Jun;98(6):1162-1173. doi: 10.1002/jnr.24576. Epub 2019 Dec 22. J Neurosci Res. 2020. PMID: 31867793 Review. - Understanding the pathogenesis of Angelman syndrome through animal models.
Jana NR. Jana NR. Neural Plast. 2012;2012:710943. doi: 10.1155/2012/710943. Epub 2012 Jul 8. Neural Plast. 2012. PMID: 22830052 Free PMC article. Review.
Cited by
- Prenatal Exposure to Azadiradione Leads to Developmental Disabilities.
Jana S, Das S, Giri B, Archak R, Bandyopadhyay S, Jana NR. Jana S, et al. Mol Neurobiol. 2024 Sep 23. doi: 10.1007/s12035-024-04493-x. Online ahead of print. Mol Neurobiol. 2024. PMID: 39312066 - Integration of CTCF loops, methylome, and transcriptome in differentiating LUHMES as a model for imprinting dynamics of the 15q11-q13 locus in human neurons.
Gutierrez Fugón OJ, Sharifi O, Heath N, Soto DC, Gomez JA, Yasui DH, Mendiola AJP, O'Geen H, Beitnere U, Tomkova M, Haghani V, Dillon G, Segal DJ, LaSalle JM. Gutierrez Fugón OJ, et al. Hum Mol Genet. 2024 Sep 19;33(19):1711-1725. doi: 10.1093/hmg/ddae111. Hum Mol Genet. 2024. PMID: 39045627 Free PMC article. - Akap5 links synaptic dysfunction to neuroinflammatory signaling in a mouse model of infantile neuronal ceroid lipofuscinosis.
Koster KP, Fyke Z, Nguyen TTA, Niqula A, Noriega-González LY, Woolfrey KM, Dell'Acqua ML, Cologna SM, Yoshii A. Koster KP, et al. Front Synaptic Neurosci. 2024 May 10;16:1384625. doi: 10.3389/fnsyn.2024.1384625. eCollection 2024. Front Synaptic Neurosci. 2024. PMID: 38798824 Free PMC article. - UBE3A: The Role in Autism Spectrum Disorders (ASDs) and a Potential Candidate for Biomarker Studies and Designing Therapeutic Strategies.
Roy B, Amemasor E, Hussain S, Castro K. Roy B, et al. Diseases. 2023 Dec 27;12(1):7. doi: 10.3390/diseases12010007. Diseases. 2023. PMID: 38248358 Free PMC article. Review. - Stem cell models of Angelman syndrome.
Camões Dos Santos J, Appleton C, Cazaux Mateus F, Covas R, Bekman EP, da Rocha ST. Camões Dos Santos J, et al. Front Cell Dev Biol. 2023 Oct 19;11:1274040. doi: 10.3389/fcell.2023.1274040. eCollection 2023. Front Cell Dev Biol. 2023. PMID: 37928900 Free PMC article. Review.
References
- Jiang YH, et al. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron. 1998;21:799–811. - PubMed
- Rougeulle C, Glatt H, Lalande M. The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nat Genet. 1997;17:14–5. - PubMed
- Schroer RJ, et al. Autism and maternally derived aberrations of chromosome 15q. Am J Med Genet. 1998;76:327–36. - PubMed
- Albrecht U, et al. Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nat Genet. 1997;17:75–8. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- T32-HD40127/HD/NICHD NIH HHS/United States
- R01 AG024492/AG/NIA NIH HHS/United States
- NS035527/NS/NINDS NIH HHS/United States
- R01 EY018323-02/EY/NEI NIH HHS/United States
- NS039402/NS/NINDS NIH HHS/United States
- R01 EY018323/EY/NEI NIH HHS/United States
- T32 HD040127/HD/NICHD NIH HHS/United States
- T32 HD040127-09/HD/NICHD NIH HHS/United States
- R01 NS039402-10/NS/NINDS NIH HHS/United States
- R01 NS035527/NS/NINDS NIH HHS/United States
- R01 NS039402/NS/NINDS NIH HHS/United States
- R01 AG024492-05/AG/NIA NIH HHS/United States
- HHMI/Howard Hughes Medical Institute/United States
- AG024492/AG/NIA NIH HHS/United States
- R01EY018323/EY/NEI NIH HHS/United States
- R01 NS035527-09/NS/NINDS NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases