Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Thalamic inhibition regulates critical-period plasticity in visual cortex and thalamus

Nature Neuroscience volume 20, pages 1715–1721 (2017)Cite this article

Subjects

Abstract

During critical periods of development, experience shapes cortical circuits, resulting in the acquisition of functions used throughout life. The classic example of critical-period plasticity is ocular dominance (OD) plasticity, which optimizes binocular vision but can reduce the responsiveness of the primary visual cortex (V1) to an eye providing low-grade visual input. The onset of the critical period of OD plasticity involves the maturation of inhibitory synapses within V1, specifically those containing the GABAA receptor α1 subunit. Here we show that thalamic relay neurons in mouse dorsolateral geniculate nucleus (dLGN) also undergo OD plasticity. This process depends on thalamic α1-containing synapses and is required for consolidation of the OD shift in V1 during long-term deprivation. Our findings demonstrate that thalamic inhibitory circuits play a central role in the regulation of the critical period. This has far-reaching consequences for the interpretation of studies investigating the molecular and cellular mechanisms regulating critical periods of brain development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Mice lacking the GABAA receptor α1 subunit have reduced OD plasticity.
Fig. 2: GABAA receptor α1 subunit expression in thalamus but not cortex is required for effective OD plasticity.
Fig. 3: Upregulation of GABAA receptor α3 and unaltered PV+ boutons in cortex of mice lacking α1.
Fig. 4: In dLGN, GABAA receptor α1 subunits increase after eye opening and are essential for synaptic inhibition.
Fig. 5: Thalamic relay neurons undergo OD plasticity.
Fig. 6: Reduced OD plasticity in dLGN neurons lacking GABAA receptor α1.

Similar content being viewed by others

References

  1. Wiesel, T. N. & Hubel, D. H. Single-cell responses in striate cortex of kittens deprived of vision in one eye. J. Neurophysiol. 26, 1003–1017 (1963).

    Article  CAS  PubMed  Google Scholar 

  2. Huang, Z. J. et al. BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell 98, 739–755 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Hensch, T. K. et al. Local GABA circuit control of experience-dependent plasticity in developing visual cortex. Science 282, 1504–1508 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fagiolini, M. & Hensch, T. K. Inhibitory threshold for critical-period activation in primary visual cortex. Nature 404, 183–186 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Hanover, J. L., Huang, Z. J., Tonegawa, S. & Stryker, M. P. Brain-derived neurotrophic factor overexpression induces precocious critical period in mouse visual cortex. J. Neurosci. 19, RC40 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Fagiolini, M. et al. Specific GABAA circuits for visual cortical plasticity. Science 303, 1681–1683 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Carulli, D. et al. Animals lacking link protein have attenuated perineuronal nets and persistent plasticity. Brain 133, 2331–2347 (2010).

    Article  PubMed  Google Scholar 

  8. Kuhlman, S. J. et al. A disinhibitory microcircuit initiates critical-period plasticity in the visual cortex. Nature 501, 543–546 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Stephany, C. E. et al. Plasticity of binocularity and visual acuity are differentially limited by nogo receptor. J. Neurosci. 34, 11631–11640 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bosman, L. W., Heinen, K., Spijker, S. & Brussaard, A. B. Mice lacking the major adult GABAA receptor subtype have normal number of synapses, but retain juvenile IPSC kinetics until adulthood. J. Neurophysiol. 94, 338–346 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Sur, C. et al. Loss of the major GABA(A) receptor subtype in the brain is not lethal in mice. J. Neurosci. 21, 3409–3418 (2001).

    CAS  PubMed  Google Scholar 

  12. Vicini, S. et al. GABA(A) receptor alpha1 subunit deletion prevents developmental changes of inhibitory synaptic currents in cerebellar neurons. J. Neurosci. 21, 3009–3016 (2001).

    CAS  PubMed  Google Scholar 

  13. Gorski, J. A. et al. Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage. J. Neurosci. 22, 6309–6314 (2002).

    CAS  PubMed  Google Scholar 

  14. Taniguchi, H. et al. A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron 71, 995–1013 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vong, L. et al. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71, 142–154 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Vue, T. Y. et al. Sonic hedgehog signaling controls thalamic progenitor identity and nuclei specification in mice. J. Neurosci. 29, 4484–4497 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Frenkel, M. Y. & Bear, M. F. How monocular deprivation shifts ocular dominance in visual cortex of young mice. Neuron 44, 917–923 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Sato, M. & Stryker, M. P. Distinctive features of adult ocular dominance plasticity. J. Neurosci. 28, 10278–10286 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ranson, A., Cheetham, C. E., Fox, K. & Sengpiel, F. Homeostatic plasticity mechanisms are required for juvenile, but not adult, ocular dominance plasticity. Proc. Natl. Acad. Sci. USA 109, 1311–1316 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kaneko, M., Stellwagen, D., Malenka, R. C. & Stryker, M. P. Tumor necrosis factor-alpha mediates one component of competitive, experience-dependent plasticity in developing visual cortex. Neuron 58, 673–680 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kralic, J. E. et al. Compensatory alteration of inhibitory synaptic circuits in cerebellum and thalamus of gamma-aminobutyric acid type A receptor alpha1 subunit knockout mice. J. Comp. Neurol. 495, 408–421 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Sommeijer, J. P. & Levelt, C. N. Synaptotagmin-2 is a reliable marker for parvalbumin positive inhibitory boutons in the mouse visual cortex. PLoS One 7, e35323 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Donato, F., Rompani, S. B. & Caroni, P. Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning. Nature 504, 272–276 (2013).

    Article  CAS  PubMed  Google Scholar 

  24. Bickford, M. E. et al. Synaptic development of the mouse dorsal lateral geniculate nucleus. J. Comp. Neurol. 518, 622–635 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Howarth, M., Walmsley, L. & Brown, T. M. Binocular integration in the mouse lateral geniculate nuclei. Curr. Biol. 24, 1241–1247 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rompani, S. B. et al. Different modes of visual integration in the lateral geniculate nucleus revealed by single-cell-initiated transsynaptic tracing. Neuron 93, 767–776.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Piscopo, D. M., El-Danaf, R. N., Huberman, A. D. & Niell, C. M. Diverse visual features encoded in mouse lateral geniculate nucleus. J. Neurosci. 33, 4642–4656 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cox, C. L., Zhou, Q. & Sherman, S. M. Glutamate locally activates dendritic outputs of thalamic interneurons. Nature 394, 478–482 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Blitz, D. M. & Regehr, W. G. Timing and specificity of feed-forward inhibition within the LGN. Neuron 45, 917–928 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Vigeland, L. E., Contreras, D. & Palmer, L. A. Synaptic mechanisms of temporal diversity in the lateral geniculate nucleus of the thalamus. J. Neurosci. 33, 1887–1896 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kuhlman, S. J., Lu, J., Lazarus, M. S. & Huang, Z. J. Maturation of GABAergic inhibition promotes strengthening of temporally coherent inputs among convergent pathways. PLOS Comput. Biol. 6, e1000797 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Linden, M. L., Heynen, A. J., Haslinger, R. H. & Bear, M. F. Thalamic activity that drives visual cortical plasticity. Nat. Neurosci. 12, 390–392 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Stellwagen, D. & Shatz, C. J. An instructive role for retinal waves in the development of retinogeniculate connectivity. Neuron 33, 357–367 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Hooks, B. M. & Chen, C. Distinct roles for spontaneous and visual activity in remodeling of the retinogeniculate synapse. Neuron 52, 281–291 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Thompson, A. D., Picard, N., Min, L., Fagiolini, M. & Chen, C. Cortical feedback regulates feedforward retinogeniculate refinement. Neuron 91, 1021–1033 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Crewther, D. P. & Crewther, S. G. A new model of strabismic amblyopia: loss of spatial acuity due to increased temporal dispersion of geniculate X-cell afferents on to cortical neurons. Vision Res. 114, 79–86 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Zhou, Y., Yu, H., Yang, Y. & Shou, T. Non-dominant eye responses in the dorsal lateral geniculate nucleus of the cat: an intracellular study. Brain Res. 987, 76–85 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Sestokas, A. K. & Lehmkuhle, S. The effects of monocular deprivation on the visual latency of geniculate X- and Y-cells in the cat. Brain Res. 395, 93–95 (1986).

    Article  CAS  PubMed  Google Scholar 

  39. Wiesel, T. N. & Hubel, D. H. Effects of visual deprivation on morphology and physiology of cells in the cats lateral geniculate body. J. Neurophysiol. 26, 978–993 (1963).

    Article  CAS  PubMed  Google Scholar 

  40. Eysel, U. T., Grüsser, O. J. & Hoffmann, K. P. Monocular deprivation and the signal transmission by X- and Y-neurons of the cat lateral geniculate nucleus. Exp. Brain Res. 34, 521–539 (1979).

    Article  CAS  PubMed  Google Scholar 

  41. Heimel, J. A., Hartman, R. J., Hermans, J. M. & Levelt, C. N. Screening mouse vision with intrinsic signal optical imaging. Eur. J. Neurosci. 25, 795–804 (2007).

    Article  PubMed  Google Scholar 

  42. Tyler, C. W., Apkarian, P., Levi, D. M. & Nakayama, K. Rapid assessment of visual function: an electronic sweep technique for the pattern visual evoked potential. Invest. Ophthalmol. Vis. Sci. 18, 703–713 (1979).

    CAS  PubMed  Google Scholar 

  43. Brainard, D. H. The psychophysics toolbox. Spat. Vis. 10, 433–436 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Harris, K. D., Henze, D. A., Csicsvari, J., Hirase, H. & Buzsáki, G. Accuracy of tetrode spike separation as determined by simultaneous intracellular and extracellular measurements. J. Neurophysiol. 84, 401–414 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Saiepour, M. H. et al. Ocular dominance plasticity disrupts binocular inhibition-excitation matching in visual cortex. Curr. Biol. 25, 713–721 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank C. Lohmann and C. Niell for the critical reading of the manuscript, E. Ruimschotel for technical assistance, and Y. Nakagawa and A. McGee for providing the Olig3-cre mouse line. This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement No. 720270 (HBP SGA1). It was further funded through a grant from AgentschapNL to the NeuroBasic PharmaPhenomics consortium (C.N.L.), a NWO grant (823.02.001) to C.N.L., a grant from Stichting Blindenhulp, a donation from Praktijkgenerator b.v., a Veni grant from the NWO to R.M. (863.12.006) and a Vidi grant from the NWO to J.A.H. (864.10.010).

Author information

Author notes

  1. Jean-Pierre Sommeijer and Mehran Ahmadlou contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Visual Plasticity, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands

    Jean-Pierre Sommeijer, M. Hadi Saiepour, Koen Seignette, Rogier Min & Christiaan N. Levelt

  2. Department of Cortical Structure and Function, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands

    Mehran Ahmadlou & J. Alexander Heimel

  3. Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, Amsterdam, The Netherlands

    Christiaan N. Levelt

Authors
  1. Jean-Pierre Sommeijer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mehran Ahmadlou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Hadi Saiepour
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Koen Seignette
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rogier Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. Alexander Heimel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christiaan N. Levelt
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.-P.S. and K.S. performed immunohistochemical analyses; J.-P.S. and M.H.S. performed intrinsic signal imaging; J.-P.S. did western blot analyses; M.A. performed the in vivo electrophysiology; R.M. performed slice electrophysiology; J.P.S., M.A., M.H.S., K.S. and R.M. conceived the experiments, performed data analyses and helped writing the manuscript; J.A.H. developed analysis tools, performed data analyses and helped with the writing; C.N.L. conceived the research line, oversaw the project and wrote the paper.

Corresponding author

Correspondence to Christiaan N. Levelt.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Integrated supplementary information.

Supplementary Figure 1 Expression of GABAA receptor α1 subunit in interneurons subsets.

a, Experimental setup. A monitor was positioned at 15 cm distance with the right half of the screen in the mouse’s right monocular visual field. 0.05 cpd drifting gratings appear in each of the quadrants of the screen. Visual stimulation of both eyes in each of the four monitor quadrants decreased reflectance of 700 nm light in different patches of left visual cortex, and response pixels are color coded (middle panel), resulting in a color coded retonotopic representation right panel). Images are the average of 15 repetitions. A region of interest (ROI) polygon was drawn covering pixels corresponding to the superior binocular visual field. A region of reference (ROR) polygon is drawn in a visually unresponsive area. b, Experimental time-line. For assessment of ocular dominance (OD) plasticity during the critical period mice were imaged at P35, and some mice were deprived from P28 to P35. c, Upper panel: α1 expression in cortical interneurons can be visualized in Gabra1fl-hom Emx1-cre+ mice. Lower panels: Expression of α1 and the interneuron markers reelin, PV, SST and VIP in cortical interneurons in Gabra1fl-hom Emx1-cre+ mice. d, Upper panels: α1 expression on the cell surface of PV+ interneurons is high. Lower panel: high α1 expression in PV + interneurons is lost in Gabra1fl-hom Gad2-cre+ mice. e, A significant OD shift is induced by 3 days of monocular deprivation of Gabra1fl-hom Gad2-cre+ Emx1-cre+ mice. t-test, P=0.008. Scale bars are 20 μm. Values shown as mean ± s.e.m. **P<0.01.

Supplementary Figure 2 Western blots of GABAA receptor components in Gabra1-/- mice and wild type littermates.

Uncropped gel runs of western blots quantified in Fig. 3. White arrows indicate the signals representing α1, α2, α3, gephyrin and γ2. Red bands are molecular weight markers, representing from top to bottom: 250, 150, 100, 37, 20, 15 and 10 kD. At the top of each lane is indicated whether the sample was from a mouse positive or negative for Gabra1.

Supplementary Figure 3 Examples and properties of binocular dLGN cells.

a, Examples of linear micro-electrode traces (red) through ipsilateral projection zone of dLGN of non-MD (left) and MD (right) wild type mice. Scale bar=500 µm. b, Top: example of clustering units based on two principal components of spike features. Bottom: waveforms of the corresponding data are represented on the right. Data colored in green belong to a single-unit. Data in blue correspond to other threshold-crossed voltage changes. c, Each row shows firing rates over time of an example cell (SU) recorded in wild type mice, while either the contralateral (red) or ipsilateral (black) eye is exposed to the full screen, 1.5s visual stimulus. The SU shown in the top row top has a very sustained response. The unit shown below has a transient response to the ipsilateral eye. The last example has an ON/OFF response to the contralateral eye and only an OFF response to the ipsilateral eye.

Supplementary Figure 4 Recordings in dLGN of Gabra1fl hom Olig3-Cre+ mice.

a, Receptive fields of MUs recorded in non MD (light green) and MD (dark green) Gabra1fl hom Olig3-Cre+ mice (n=41 and 25 MUs, respectively). The position of the nose of the mouse is at horizontal and vertical 0 cm. The red dashed lines indicate -30o and +30o horizontal angles. b, Examples of linear micro-electrode traces (red) through ipsilateral projection zone of dLGN of non-MD (left) and MD (right panels) Gabra1fl-hom Olig3-cre+ mice, stained by DAPI (blue). White line delineates dLGN. Scale bar=500 µm.

Supplementary information.

Supplementary Text and Figures

Supplementary Figures 1–4

Life Sciences Reporting Summary

Supplementary Tables

Supplementary Tables 1 and 2

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sommeijer, JP., Ahmadlou, M., Saiepour, M.H. et al. Thalamic inhibition regulates critical-period plasticity in visual cortex and thalamus. Nat Neurosci 20, 1715–1721 (2017). https://doi.org/10.1038/s41593-017-0002-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41593-017-0002-3

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing