Loss of Arc renders the visual cortex impervious to the effects of sensory experience or deprivation

Journal name:
Nature Neuroscience
Volume:
13,
Pages:
450–457
Year published:
DOI:
doi:10.1038/nn.2508
Received
Accepted
Published online

Abstract

A myriad of mechanisms have been suggested to account for the full richness of visual cortical plasticity. We found that visual cortex lacking Arc is impervious to the effects of deprivation or experience. Using intrinsic signal imaging and chronic visually evoked potential recordings, we found that Arc−/− mice did not exhibit depression of deprived-eye responses or a shift in ocular dominance after brief monocular deprivation. Extended deprivation also failed to elicit a shift in ocular dominance or open-eye potentiation. Moreover, Arc−/− mice lacked stimulus-selective response potentiation. Although Arc−/− mice exhibited normal visual acuity, baseline ocular dominance was abnormal and resembled that observed after dark-rearing. These data suggest that Arc is required for the experience-dependent processes that normally establish and modify synaptic connections in visual cortex.

At a glance

Figures

  1. Loss of Arc does not affect V1 responsiveness and organization.
    Figure 1: Loss of Arc does not affect V1 responsiveness and organization.

    (a) Intrinsic signal imaging of V1 (left) in wild-type and Arc−/− mice. Top, ocular dominance map of V1 in a wild-type mouse (WT, left) and an Arc−/− mouse (right). BZ, binocular zone; MZ, monocular zone. Scale illustrates binocularity index of pixels. Scale bar represents 500 μm. V1 in Arc−/− mice was similar to that in wild-type mice in total area (wild type, n = 6, area = 1.401 ± 0.07 mm2; Arc−/−, n = 10, area = 1.270 ± 0.15 mm2; P > 0.5, t test). Bottom, retinotopic organization of V1 in a wild-type mouse (left) and an Arc−/− mouse (right). Each image shows the mapping of elevation according to the scale bar on the right. (b) Scatter analysis of 50 × 50 pixel area in white box in A for wild-type and Arc−/− mice. The receptive field center (phase) differences between sets of five adjacent pixels are shown in the histograms on the right. The precision of local mapping was comparable between wild-type and Arc−/− mice.

  2. Intrinsic signal imaging after monocular deprivation illustrates a requirement for Arc in deprived-eye depression after short-term monocular deprivation.
    Figure 2: Intrinsic signal imaging after monocular deprivation illustrates a requirement for Arc in deprived-eye depression after short-term monocular deprivation.

    (a) Top, monocular deprivation was initiated near the peak of the critical period for 3–4 d. Control mice were age-matched to deprived mice. Bottom, ODIs for individual mice are shown as circles. Horizontal bars represent group averages (wild type: control, n = 9, ODI = 0.28 ± 0.03; deprived, n = 14, ODI = −0.05 ± 0.03, P < 0.0001, t test; Arc−/−: control, n = 10, ODI = 0.19 ± 0.02; deprived, n = 11, ODI = 0.13 ± 0.02, P > 0.1, t test). (b) Response magnitude in wild-type mice driven by the contralateral eye and ipsilateral eye, plotted as average ΔR/R × 10−3. There was a depression in the contralateral eye response amplitude (control = 2.9 ± 0.27, deprived = 1.62 ± 0.23, *P < 0.001, t test). No change in the ipsilateral eye response was detected (control = 1.56 ± 0.21, deprived = 1.68 ± 0.19, P > 0.8, t test). (c) No change in contralateral response occurred in Arc−/− mice after deprivation (control = 2.25 ± 0.28, deprived = 2.5 ± 0.26, P > 0.2, t test); similarly, no change in ipsilateral response was detected (control = 1.35 ± 0.23, deprived = 1.64 ± 0.19, P > 0.2, t test). ΔR/R is the change in reflectance over baseline reflectance. Error bars represent s.e.m.

  3. Chronic VEP recordings show that Arc-/- mice do not exhibit ocular dominance plasticity after short-term monocular deprivation.
    Figure 3: Chronic VEP recordings show that Arc−/− mice do not exhibit ocular dominance plasticity after short-term monocular deprivation.

    (a) Wild-type mice exhibited a significant depression in contralateral (deprived eye) responses (n = 11; day 0 = 149 ± 8.8 μV, 3-d monocular deprivation = 75.4 ± 8.8 μV, *P << 0.0001, paired t test). No significant change was observed in ipsilateral responses (n = 11; day 0 = 70.4 ± 6.4 μV, 3-d monocular deprivation = 68.8 ± 8 μV, P > 0.8, paired t test). Averaged waveforms across all mice are shown at top. MD, monocular deprivation. (b) Arc−/− mice exhibited no changes in contralateral responses (n = 8; day 0 = 121 ± 14.7 μV, 3-d monocular deprivation = 111.3 ± 13.5 μV, P > 0.2, paired t test) or in ipsilateral responses (n = 8; day 0 = 92.5 ± 15 μV, 3-d monocular deprivation = 85.8 ± 10.7 μV, P > 0.7, paired t test). Averaged waveforms are shown at top. (c) Wild-type mice exhibited a significant shift in the contralateral to ipsilateral eye ratio (n = 11; day 0 = 2.2 ± 0.16, 3-d monocular deprivation = 1.2 ± 0.16, *P << 0.0001, paired t test), whereas Arc−/− mice exhibited no significant shift in the contralateral to ipsilateral eye ratio (n = 8; day 0 = 1.4 ± 0.12, 3-d monocular deprivation = 1.5 ± 0.33, P > 0.8, paired t test). Arc−/− mice exhibited a significantly smaller baseline contralateral to ipsilateral eye ratio than wild-type mice (wild type, n = 11, contralateral to ipsilateral eye ratio 2.22 ± 0.16; Arc−/−, n = 8, contralateral to ipsilateral eye ratio 1.37 ± 0.12, #P < 0.001, t test). Error bars represent s.e.m.

  4. Arc is required for the decrease in surface AMPARs after short-term monocular deprivation.
    Figure 4: Arc is required for the decrease in surface AMPARs after short-term monocular deprivation.

    (a) Schematic of mouse brain showing the segments of V1 dissected for biochemical analysis. Because V1 is dominated by contralateral eye responses, cortex contralateral to the deprived eye was termed 'deprived' and cortex ipsilateral to the deprived eye was termed 'control'. (b) Example immunoblots of total and biotinylated surface proteins in the visual cortex of Arc−/− and wild-type mice. Full blots are presented in Supplementary Figure 6. GAPDH was used as an internal control to show that biotin specifically labeled surface proteins. In addition, a control image (bottom) shows the specificity of the biotinylation assay. No band can be detected in the surface lane of protein samples that were not exposed to biotin. (c) Summary of changes in surface and total protein levels occurring after deprivation (wild type, n = 5; Arc−/−, n = 7). Surface levels of GluR1 were significantly lower in the deprived hemisphere of wild-type mice than in controls (*P < 0.0001, t test) but not in Arc−/− mice (P > 0.2, t test). Error bars represent s.e.m.

  5. Arc-/- mice do not show a shift in ocular dominance after extended deprivation, as assessed by intrinsic signal imaging.
    Figure 5: Arc−/− mice do not show a shift in ocular dominance after extended deprivation, as assessed by intrinsic signal imaging.

    (a) Top, monocular deprivation was initiated near the peak of the critical period for 7 d. Control mice were age-matched to deprived mice. ODIs for individual mice are shown as circles. Horizontal bars represent group averages (wild type: control, n = 9, ODI = 0.28 ± 0.03; deprived, n = 7, ODI = −0.063 ± 0.02, *P < 0.0001; Arc−/−: control, n = 10, ODI = 0.19 ± 0.02; deprived, n = 8, ODI = 0.13 ± 0.02, P = 0.17). (b) Response magnitude in wild-type mice driven by the contralateral eye and ipsilateral eye, plotted as average ΔR/R × 10−3. Some depression was observed in the contralateral eye response amplitude, although it was not significant (control = 2.9 ± 0.27, deprived = 2.1 ± 0.23, P > 0.05). Lid suture resulted in an increase in the ipsilateral eye response (control = 1.56 ± 0.21, deprived = 2.49 ± 0.17, *P < 0.05). (c) No change in contralateral response occurred in Arc−/− mice after deprivation (control = 2.25 ± 0.28, deprived = 2.2 ± 0.21, P > 0.6); similarly, no change was detected in ipsilateral response (control = 1.35 ± 0.23, deprived = 1.5 ± 0.21, P > 0.6). ΔR/R is the change in reflectance over baseline reflectance. Error bars represent s.e.m. Statistical analyses for ac conducted using one-way ANOVA with Bonferroni correction.

  6. Arc-/- mice exhibit no ocular dominance plasticity as assessed by chronic VEP recordings after long-term monocular deprivation.
    Figure 6: Arc−/− mice exhibit no ocular dominance plasticity as assessed by chronic VEP recordings after long-term monocular deprivation.

    (a) Wild-type mice exhibited a significant depression in contralateral (deprived eye) responses (n = 7; day 0 = 152 ± 9.2 μV, 7-d monocular deprivation = 89.5 ± 11.5 μV, *P < 0.003, paired t test) and a significant potentiation in ipsilateral responses (n = 7; day 0 = 84.9 ± 9.8 μV, 7-d monocular deprivation = 114.2 ± 10.1 μV, #P < 0.05, paired t test). Averaged waveforms are shown at top. (b) Arc−/− mice exhibited no changes in contralateral (n = 6; day 0 = 112 ± 2.2 μV, 7-d monocular deprivation = 100 ± 6 μV, P > 0.1, paired t test) or in ipsilateral responses (n = 8; day 0 = 96 ± 8.6 μV, 3-d monocular deprivation = 84 ± 10 μV, P > 0.4, paired t test). Averaged waveforms are shown at top. (c) Wild-type mice exhibited a significant shift in the contralateral to ipsilateral eye ratio (n = 7; day 0 = 1.9 ± 0.14, 7-d monocular deprivation = 0.8 ± 0.06, *P < 0.0001, paired t test), whereas the contralateral to ipsilateral eye ratio did not significantly shift in Arc−/− mice (n = 6; day 0 = 1.2 ± 0.1, 7-d monocular deprivation = 1.25 ± 0.11, P > 0.7, paired t test). Arc−/− mice had a significantly smaller baseline contralateral to ipsilateral eye ratio than wild-type mice (wild type n = 7, contralateral to ipsilateral eye ratio 1.87 ± 0.14; Arc−/− n = 6, contralateral to ipsilateral eye ratio 1.2 ± 0.1, #P < 0.003). Error bars represent s.e.m.

  7. Dark-rearing wild-type mice from birth mimics the contralateral to ipsilateral ratio observed Arc-/- mice.
    Figure 7: Dark-rearing wild-type mice from birth mimics the contralateral to ipsilateral ratio observed Arc−/− mice.

    (a) Arc−/− and dark-reared (DR) mice both had significant decreases in the contralateral to ipsilateral eye ratio in layer 4 VEPs as compared with wild-type mice (wild type: n = 16, 2.1 ± 0.1; Arc−/−: n = 16, 1.35 ± 0.08, *P << 0.0001, t test; dark-reared: n = 11, 1.29 ± 0.1, *P << 0.0001, t test). (b) The change in ocular dominance ratio in Arc−/− and dark-reared mice was mainly the result of a significant depression in contralateral (C) responses (wild type, 146 ± 6 μV; Arc−/−, 116 ± 7 μV, *P < 0.006, t test; dark reared, 74 ± 9 μV, **P << 0.0001, t test), as ipsilateral responses (I) were not significantly different (wild type, 72 ± 5 μV; Arc−/−, 90 ± 8 μV, P > 0.07, t test; dark reared, 59 ± 8 μV, P > 0.2, t test). Error bars represent s.e.m.

  8. Arc-/- mice lack stimulus-selective response potentiation (SRP), whereas dark-reared mice exhibit enhanced SRP in V1.
    Figure 8: Arc−/− mice lack stimulus-selective response potentiation (SRP), whereas dark-reared mice exhibit enhanced SRP in V1.

    (a) Wild-type mice exhibited large and sustained potentiation of binocular VEPs over many days of exposure to the same stimulus orientation (n = 11, day 1 = 195 ± 10 μV, day 6 = 369 ± 14 μV, P << 0.0001, paired t test). Responses to a control orthogonal stimulus (90°, open black circle) shown at day 6 were not significantly potentiated (day 6 (90°) = 170 ± 9 μV, P > 0.09, t test). Dark-reared mice had small VEPs at baseline, which became markedly potentiated after exposure to the same stimulus orientation (n = 12, day 1 = 83 ± 9 μV, day 6 = 304 ± 43 μV, P < 0.001, paired t test). Responses to a control orthogonal stimulus (90°, open red triangle) were significantly increased compared with baseline VEPs (day 6 (90°) = 161 ± 29 μV, P < 0.03, t test) but were also significantly smaller than the SRP orientation at day 6 (P < 0.04). In contrast, we did not observe significant potentiation of responses to the same stimulus in Arc−/− mice (n = 16, day 1 = 170 ± 9 μV, day 6 = 180 ± 23 μV, P > 0.7, paired t test). Responses to the control orthogonal stimulus (90°, blue square) were also not significantly different from baseline (day 6 (90°) = 159 ± 12 μV, P > 0.1, t test), suggesting that there was no general decrease in responses over time. (b) VEPs normalized to baseline values indicated that there was a relative enhancement of potentiation as compared in dark-reared compared with light-reared mice, whereas Arc−/− mice had no relative potentiation of VEPs. (c) Average VEP waveforms at baseline (day 1) and after 5 d of repeated exposure to the same orientation (day 6).

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Author information

  1. These authors contributed equally to this work.

    • Cortina L McCurry &
    • Jason D Shepherd

Affiliations

  1. Department of Brain and Cognitive Sciences, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Cortina L McCurry,
    • Jason D Shepherd,
    • Daniela Tropea,
    • Mark F Bear &
    • Mriganka Sur
  2. Department of Brain and Cognitive Sciences, The Picower Institute for Learning and Memory, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Jason D Shepherd &
    • Mark F Bear
  3. National Institute of Mental Health, Bethesda, Maryland, USA.

    • Kuan H Wang

Contributions

C.L.M. and J.D.S. conducted experiments and data analysis and wrote the manuscript. D.T. assisted with optical imaging experiments. K.H.W. provided the Arc−/− mouse line. M.S. and M.F.B. helped design experiments and supervised the project.

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The authors declare no competing financial interests.

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