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

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

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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.

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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.

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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).

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  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

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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.

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Correspondence to Christiaan N. Levelt.

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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.

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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

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