Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Mar 23;107(12):5611-6.
doi: 10.1073/pnas.1001281107. Epub 2010 Mar 8.

Genomic imprinting of experience-dependent cortical plasticity by the ubiquitin ligase gene Ube3a

Masaaki Sato  1 , Michael P Stryker
Affiliations

Genomic imprinting of experience-dependent cortical plasticity by the ubiquitin ligase gene Ube3a

Masaaki Sato et al. Proc Natl Acad Sci U S A. .

Abstract

A defect in the maternal copy of a ubiqutin ligase gene Ube3a can produce a neurodevelopmental defect in human children known as Angelman syndrome. We investigated the role of the maternally expressed Ube3a gene in experience-dependent development and plasticity of the mouse visual system. As demonstrated by optical imaging, rapid ocular dominance (OD) plasticity after brief monocular deprivation (MD) was severely impaired during the critical period (CP) in the visual cortex (VC) of Ube3a maternal-deficient (m-/p+) mice. Prolonged MD elicited significant plasticity in m-/p+ mice that never matched the level seen in control animals. In older animals after the CP, 7-day MD elicited mild OD shifts in both control and m-/p+ mice; however, the OD shifts in m-/p+ mice lacked the strengthening of visual responses to the two eyes characteristic of normal adult plasticity. Anatomic effects of the maternal deficiency include reduced spine density on basal, but not apical, dendrites of pyramidal neurons in the binocular region of the VC. Imprinting of Ube3a expression was not fully established in the early postnatal period, consistent with the normal development of cortical retinotopy and visual acuity that we observed in m-/p+ mice, but was fully established by the onset of the CP. These results demonstrate that paternal and maternal genomes are not functionally equivalent for cortical plasticity, and that maternally expressed Ube3a is required for normal experience-dependent modification of cortical circuits during and after the CP.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Imprinting and localization of Ube3a protein in juvenile mouse VC. (A) Imprinted expression of Ube3a in juvenile mouse VC. Confocal images of Ube3a immunofluorescence (i, iii, and v) and DAPI nuclear staining (ii, iv, and vi) in VC of wild-type (m+/p+), paternal-deficient (m+/p−) and maternal-deficient (m−/p+) mice at P27–29. Cortical layers are indicated in Roman numerals on the right of the DAPI images. (Scale bar: 200 μm.) (B) Expression of Ube3a in excitatory neurons. Arrows and arrowheads show Ube3a immunoreactivity in a few representative CaMKII-positive principal neurons and CaMKII-negative neurons, respectively. (Scale bar: 50 μm.) (C) Expression of Ube3a in inhibitory neurons. Arrows and arrowheads indicate Ube3a immunoreactivity in GAD67-negative neurons and GAD67-positive neurons, respectively. (Scale bar: 50 μm.) (D) Immunoblot analysis of Ube3a protein in VC (i) and prefrontal cortex (PFC; ii). Molecular sizes of marker proteins are indicated on the right. β-tubulin III (β-TubIII) was used as a loading control. Bar graphs show quantification of the Ube3a protein levels expressed as a percentage of those in m+/p+ mice (n = 3).
Fig. 2.
Fig. 2.
Lack of rapid OD plasticity after brief MD and effects of prolonged MD during and after CP in m−/p+ mice. (A) OD shifts after brief and prolonged MD in m−/p+ and m+/p+ mice at the peak of CP. It requires 14d MD in m−/p+ mice (closed circles) to elicit OD shifts that are comparable to those in m+/p+ mice (open circles) after only 4d MD. Plasticity is significantly less in m−/p+ mice than in m+/p+ mice with corresponding durations of MD (n = 8–9; **P < 0.01 vs. m+/p+). (B) Response magnitude maps for the contralateral (C) or ipsilateral (I) eye before (pre-MD) and after 4d and 14d MD in m+/p+ and m−/p+ mice at the age of CP. (C) OD shifts elicited by 7d MD in m+/p+ (open circles) and m−/p+ (closed circles) mice after the CP (post-CP) beginning at P33–37 (n = 5–7; **P < 0.01, m+/p+ at pre-MD vs. m+/p+ at 7d MD; ##P < 0.01, m−/p+ at pre-MD vs. m−/p+ at 7d MD). (D) Maximum magnitude of eye-specific responses for the contralateral (contra, Left) and ipsilateral (ipsi, Right) eyes before and after 4d and 7d MD in m+/p+ (open circles) and m−/p+ (closed circles) mice at the age of post-CP (n = 5–7; **P < 0.01). (E) Net OD shifts elicited by brief (4d) MD during CP and after (post-CP) in m+/p+ (white bars) and m−/p+ mice (black bars) (n = 5–9; **P < 0.01, m−/p+ vs. m+/p+ in CP; #P < 0.05, CP vs. post-CP in the same genotype). (F) Response magnitude maps for the contralateral or ipsilateral eye before (pre-MD) and after 4d and 7d MD in m+/p+ and m−/p+ mice at post-CP.
Fig. 3.
Fig. 3.
Subcellular domain–specific reduction of spine density in layer 5 pyramidal neurons in binocular cortex of m−/p+ mice. (A) m−/p+ mice bearing GFP-labeled infragranular cortical neurons were genetically obtained from the offspring of female Ube3a heterozygotes crossed with male homozygous thy1-GFP transgenic mice. (B) Locating binocular VC by optical imaging. Visual response was evoked through the ipsilateral eye by a noise movie presented in binocular visual field. The image of cortical activity was superimposed onto a vasculature image taken under green illumination, R, rostral; L, lateral. (Scale bar: 1 mm.) (C) GFP-labeled infragranular pyramidal neurons (open arrowheads) in binocular zone of the m−/p+ mouse shown in B. Boundaries of the binocular cortex are designated by red tracks of DiI. hp, hippocampus; D, dorsal; L, lateral. (Scale bar: 250 μm.) (D) Examples of GFP-labeled layer 5 pyramidal neurons in binocular VC of m+/p+ (a and c) and m−/p+ (b and d) mice. (Scale bar: 20 μm.) (E and F) Maximum intensity projections (MIPs) of secondary apical dendrites of layer 5 pyramidal neurons in m+/p+ (E) and m−/p+ (F) binocular VC. (G and H) MIPs of basal dendrites of layer 5 pyramidal neurons in m+/p+ (G) and m−/p+ (H) binocular VC. (Scale bar: 5 μm.) (I) Quantitative analysis of spine density showing that layer 5 pyramidal neurons in m−/p+ mice have significantly reduced spine density in basal dendrites, but not in apical dendrites (n = 13 each; *P < 0.05; ns, not significant). (J) Thickness of binocular VC in m+/p+ (white bar, n = 3) and m−/p+ mice (black bar, n = 3). (K) Overall cell density in lower layer 2/3 and layer 5 of binocular VC in m+/p+ (white bars, n = 3) and m−/p+ mice (black bars, n = 3).
Fig. 4.
Fig. 4.
Relaxed imprinting of Ube3a expression in early postnatal VC in mice. (A) Confocal images of Ube3a immunofluorescence (i and iii), control fluorescence without primary antibody against Ube3a (v), and DAPI nuclear staining (ii, iv, and vi) in VC of m+/p+ (i and ii) and m−/p+ mice (iii–vi) at P6. Neurons in m−/p+ mice exhibit weak, but specific, labeling for Ube3a. Cortical layers are indicated in Roman numerals on the right of the DAPI images. (Scale bar: 100 μm.) (B) Expression of Ube3a protein in inhibitory neurons during the early postnatal period. Ube3a immunoreactivity in GAD67-positive and GAD67-negative neurons is indicated by arrowheads and arrows, respectively. (Scale bar: 20 μm.) (C) Immunoblot analysis of Ube3a protein expression, as shown in Fig. 1D, in VC of m+/p+ and m−/p+ mice at P6. Quantification of Ube3a levels in VC of m−/p+ mice at P6 is shown on the right (n = 4).
Fig. 5.
Fig. 5.
Imprinting of Ube3a and its role in mouse visual development. (See Discussion for details.)
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Wilkinson LS, Davies W, Isles AR. Genomic imprinting effects on brain development and function. Nat Rev Neurosci. 2007;8:832–843. - PubMed
    1. McGrath J, Solter D. Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell. 1984;37:179–183. - PubMed
    1. Barton SC, Surani MA, Norris ML. Role of paternal and maternal genomes in mouse development. Nature. 1984;311:374–376. - PubMed
    1. Allen ND, et al. Distribution of parthenogenetic cells in the mouse brain and their influence on brain development and behavior. Proc Natl Acad Sci USA. 1995;92:10782–10786. - PMC - PubMed
    1. Keverne EB, Fundele R, Narasimha M, Barton SC, Surani MA. Genomic imprinting and the differential roles of parental genomes in brain development. Brain Res Dev Brain Res. 1996;92:91–100. - PubMed

Publication types

Substances