Structural basis for the role of inhibition in facilitating adult brain plasticity

Journal name:
Nature Neuroscience
Volume:
14,
Pages:
587–594
Year published:
DOI:
doi:10.1038/nn.2799
Received
Accepted
Published online

Abstract

Although inhibition has been implicated in mediating plasticity in the adult brain, the underlying mechanism remains unclear. Here we present a structural mechanism for the role of inhibition in experience-dependent plasticity. Using chronic in vivo two-photon microscopy in the mouse neocortex, we show that experience drives structural remodeling of superficial layer 2/3 interneurons in an input- and circuit-specific manner, with up to 16% of branch tips undergoing remodeling. Visual deprivation initially induces dendritic branch retractions, and this is accompanied by a loss of inhibitory inputs onto neighboring pyramidal cells. The resulting decrease in inhibitory tone, also achievable pharmacologically using the antidepressant fluoxetine, provides a permissive environment for further structural adaptation, including addition of new synapse-bearing branch tips. Our findings suggest that therapeutic approaches that reduce inhibition, when combined with an instructive stimulus, could facilitate restructuring of mature circuits impaired by damage or disease, improving function and perhaps enhancing cognitive abilities.

At a glance

Figures

  1. Chronic two-photon in vivo imaging of dendritic branch tip dynamics in superficial L2/3 cortical interneurons.
    Figure 1: Chronic two-photon in vivo imaging of dendritic branch tip dynamics in superficial L2/3 cortical interneurons.

    (a) Experimental time course. Every cell was imaged at all indicated time points. (b) Maximum z projection (MZP) of chronically imaged interneuron (green arrow) superimposed over intrinsic signal map of monocular (V1M) and binocular (V1B) visual cortex. (c) Coronal section of primary visual cortex (V1) containing an imaged superficial L2/3 interneuron (~70 μm below the pial surface; green arrow) shown with respect to V1M and V1B as identified through WGA–Alexa 555 (WGA-555) labeling of thalamacortical projections from the ipsilateral eye (red) and DAPI staining of the granule cell layer (blue). (d) MZPs near the cell body (above) along with two-dimensional projections of three-dimensional skeletal reconstructions (below) of a superficial L2/3 interneuron (~85 μm below the pial surface) in V1B acquired at the specified intervals. Dendritic branch tip elongations and retractions identified between successive imaging sessions are indicated by blue and red arrows, respectively. (e) High-magnification view of one branch tip elongation (orange box in d). Blue arrow marks the approximate distal end of the branch tip at −14 d. (f) High-magnification view of one branch tip retraction (magenta box in d). Red arrow marks the approximate distal end of the branch tip at 0 d. Scale bars: b, 250 μm; c, 100 μm; d, 50 μm; e,f, 5 μm.

  2. Monocular deprivation increases interneuron dendritic branch tip dynamics in adult binocular visual cortex.
    Figure 2: Monocular deprivation increases interneuron dendritic branch tip dynamics in adult binocular visual cortex.

    (a,b) Dendritic branch tip dynamics in superficial L2/3 interneurons imaged throughout a 14-d monocular deprivation for binocular visual cortex (individual cells shown in gray, mean shown in magenta; n = 16 cells from 13 mice, 524 branch tips) (a) and monocular visual cortex (individual cells shown in gray, mean shown in blue; n = 12 cells from 12 mice, 461 branch tips) (b). (c) Rate of dendritic branch tip dynamics compared before and during monocular deprivation in binocular (magenta) and monocular (blue) visual cortex. (d) Cumulative fraction of dynamic branch tips in binocular visual cortex over imaging time course (**P < 0.01, *P < 0.05). Error bars, s.e.m.

  3. Synapses are formed on newly extended branch tips.
    Figure 3: Synapses are formed on newly extended branch tips.

    (a) In vivo image of a branch tip elongation. Blue arrow marks the approximate distal end of the branch tip at −14 d. (b) Reidentification of the same imaged dendrite in fixed tissue after immunostaining for GFP. (c) High-magnification view of dendritic portion reconstructed by serial section electron microscopy (white box in b). (d) Serial section electron microscopy reconstruction of the in vivo–imaged dendrite (in green) with region proximal to (yellow arrows in ac) and very distal portion of (red arrows in ac) elongated branch tip. Left, contacting axon terminals (in blue); right, synaptic contacts (in blue). (e,f) Electron micrographs showing a synapse on the newly elongated branch tip (e arrow in d) and on the proximal, stable dendrite (f arrow in d), respectively. Bottom panels show an enlargement of the synapse with visible synaptic cleft (red arrows) and synaptic vesicles. Scale bars: a,b, 5 μm; c, 2 μm; d, 1 μm; e,f, top, 500 nm; bottom, 100 nm.

  4. Monocular deprivation induces laminar-specific dendritic arbor rearrangements.
    Figure 4: Monocular deprivation induces laminar-specific dendritic arbor rearrangements.

    (a) Distribution of dynamic branch tips before and during monocular deprivation in binocular visual cortex. Plotted are cell soma positions (black circles) and branch tip positions of branch tip elongations (blue) or retractions (red). (b) Cumulative fraction distribution plot of branch tip elongations (blue) and retractions (red) from 0–4 d MD (left) and 4–7 d MD (right) as compared to control (dotted lines) (*P < 0.05). (c) Rate of dendritic branch tip elongations (blue) and retractions (red) in L1 and L2/3 of binocular visual cortex, before and during monocular deprivation (n = 16 cells from 13 mice; L1, 228 branch tips; L2/3, 325 branch tips) (**P < 0.01, *P < 0.05). Error bars, s.e.m.

  5. Binocular deprivation specifically increases retractions of L2/3 branch tips.
    Figure 5: Binocular deprivation specifically increases retractions of L2/3 branch tips.

    (a) Dendritic branch tip dynamics compared before and during binocular deprivation in binocular visual cortex. (b) Rate of branch tip elongations (blue) and retractions (red) in L1 and L2/3 of binocular visual cortex, before and during binocular deprivation (n = 7 cells from 7 mice; L1, 108 branch tips; L2/3, 155 branch tips; # denotes a time point measurement equaling 0 ± 0.00% dynamic branch tips per week) (**P < 0.02, *P < 0.05). Error bars, s.e.m.

  6. Four days of monocular deprivation increases inhibitory synapse elimination onto L5 pyramidal apical dendrites.
    Figure 6: Four days of monocular deprivation increases inhibitory synapse elimination onto L5 pyramidal apical dendrites.

    (a) High-magnification view of axonal bouton remodeling of superficial L2/3 interneuron. Yellow arrows indicate stable boutons and red arrow an eliminated bouton. (b) Fraction of total axonal boutons added or eliminated during normal vision or in response to 4 d of monocular deprivation (n = 6 cells from 6 mice, 564 axonal boutons) (**P < 0.01, *P < 0.05). (c) Coronal section of a GFP-labeled L2/3 pyramidal neuron in binocular visual cortex (in green) after immunohistochemical staining of inhibitory presynaptic terminals by VGAT (in red). Examples of inhibitory presynaptic contacts onto dendritic (top right) and perisomatic (bottom right) synapses are indicated with white arrows. (d) Quantification of putative inhibitory synapse density on L2/3 pyramidal neuron soma and on dendrites of L2/3 and L5 pyramidal neurons in binocular visual cortex after 4 d of monocular deprivation (4 d MD) (control, n = 8 mice, 49 L2/3 pyramidal neurons, 45 L5 pyramid neurons, 9,688 synapses; 4 d MD, n = 8, 46 L2/3 pyramidal neurons, 39 L5 pyramid neurons, 8,581 synapses) (*P < 0.05). Error bars, s.e.m. Scale bars: a,c, right, 2 μm; c, left, 5 μm.

  7. Reduction in intracortical inhibition by fluoxetine treatment promotes experience-dependent branch tip remodeling.
    Figure 7: Reduction in intracortical inhibition by fluoxetine treatment promotes experience-dependent branch tip remodeling.

    (a) Experimental time course. (b) High-magnification view of one branch tip retraction during fluoxetine treatment. Red arrow marks the approximate distal end of the branch tip at −28 d. Scale bar, 10 μm. (c) Dendritic branch tip dynamics in L1 and L2/3 of binocular visual cortex of animals under normal vision before and during fluoxetine administration. Rates of L2/3 branch tip elongations and retractions in binocular visual cortex during fluoxetine treatment under normal vision or a brief (4-d) monocular deprivation (0–4 d MD) as compared to prolonged (7-d) monocular deprivation (4–7 d MD) without fluoxetine treatment (taken from Fig. 4c) (with fluoxetine: n = 8 cells from 8 mice; L1, 113 branch tips; L2/3, 115 branch tips; without fluoxetine: n = 16 cells from 13 mice; L2/3, 325 branch tips) (**P < 0.01; *P < 0.05). Error bars, s.e.m.

References

  1. Rubenstein, J.L. & Merzenich, M.M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255267 (2003).
  2. Dani, V.S. et al. Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc. Natl. Acad. Sci. USA 102, 1256012565 (2005).
  3. Kleschevnikov, A.M. et al. Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. J. Neurosci. 24, 81538160 (2004).
  4. Fernandez, F. et al. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat. Neurosci. 10, 411413 (2007).
  5. Harauzov, A. et al. Reducing intracortical inhibition in the adult visual cortex promotes ocular dominance plasticity. J. Neurosci. 30, 361371 (2010).
  6. He, H.Y., Hodos, W. & Quinlan, E.M. Visual deprivation reactivates rapid ocular dominance plasticity in adult visual cortex. J. Neurosci. 26, 29512955 (2006).
  7. Maya Vetencourt, J.F. et al. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science 320, 385388 (2008).
  8. Sale, A. et al. Environmental enrichment in adulthood promotes amblyopia recovery through a reduction of intracortical inhibition. Nat. Neurosci. 10, 679681 (2007).
  9. Lee, W.C. et al. Dynamic remodeling of dendritic arbors in GABAergic interneurons of adult visual cortex. PLoS Biol. 4, e29 (2006).
  10. Lee, W.C. et al. A dynamic zone defines interneuron remodeling in the adult neocortex. Proc. Natl. Acad. Sci. USA 105, 1996819973 (2008).
  11. Daw, N.W., Fox, K., Sato, H. & Czepita, D. Critical period for monocular deprivation in the cat visual cortex. J. Neurophysiol. 67, 197202 (1992).
  12. LeVay, S., Wiesel, T.N. & Hubel, D.H. The development of ocular dominance columns in normal and visually deprived monkeys. J. Comp. Neurol. 191, 151 (1980).
  13. Hirsch, J.A. & Gilbert, C.D. Long-term changes in synaptic strength along specific intrinsic pathways in the cat visual cortex. J. Physiol. (Lond.) 461, 247262 (1993).
  14. Frenkel, M.Y. et al. Instructive effect of visual experience in mouse visual cortex. Neuron 51, 339349 (2006).
  15. Hofer, S.B., Mrsic-Flogel, T.D., Bonhoeffer, T. & Hubener, M. Prior experience enhances plasticity in adult visual cortex. Nat. Neurosci. 9, 127132 (2006).
  16. Hofer, S.B., Mrsic-Flogel, T.D., Bonhoeffer, T. & Hubener, M. Experience leaves a lasting structural trace in cortical circuits. Nature 457, 313317 (2009).
  17. Sato, M. & Stryker, M.P. Distinctive features of adult ocular dominance plasticity. J. Neurosci. 28, 1027810286 (2008).
  18. Sawtell, N.B. et al. NMDA receptor-dependent ocular dominance plasticity in adult visual cortex. Neuron 38, 977985 (2003).
  19. Kameyama, K. et al. Difference in binocularity and ocular dominance plasticity between GABAergic and excitatory cortical neurons. J. Neurosci. 30, 15511559 (2010).
  20. Nassi, J.J. & Callaway, E.M. Parallel processing strategies of the primate visual system. Nat. Rev. Neurosci. 10, 360372 (2009).
  21. Bullier, J., Hupe, J.M., James, A.C. & Girard, P. The role of feedback connections in shaping the responses of visual cortical neurons. Prog. Brain Res. 134, 193204 (2001).
  22. Maunsell, J.H. & van Essen, D.C. The connections of the middle temporal visual area (MT) and their relationship to a cortical hierarchy in the macaque monkey. J. Neurosci. 3, 25632586 (1983).
  23. Antonini, A., Fagiolini, M. & Stryker, M.P. Anatomical correlates of functional plasticity in mouse visual cortex. J. Neurosci. 19, 43884406 (1999).
  24. Dong, H., Shao, Z., Nerbonne, J.M. & Burkhalter, A. Differential depression of inhibitory synaptic responses in feedforward and feedback circuits between different areas of mouse visual cortex. J. Comp. Neurol. 475, 361373 (2004).
  25. Yamashita, A., Valkova, K., Gonchar, Y. & Burkhalter, A. Rearrangement of synaptic connections with inhibitory neurons in developing mouse visual cortex. J. Comp. Neurol. 464, 426437 (2003).
  26. Frenkel, M.Y. & Bear, M.F. How monocular deprivation shifts ocular dominance in visual cortex of young mice. Neuron 44, 917923 (2004).
  27. Gordon, J.A. & Stryker, M.P. Experience-dependent plasticity of binocular responses in the primary visual cortex of the mouse. J. Neurosci. 16, 32743286 (1996).
  28. Wiesel, T.N. & Hubel, D.H. Comparison of the effects of unilateral and bilateral eye closure on cortical unit responses in kittens. J. Neurophysiol. 28, 10291040 (1965).
  29. Silberberg, G., Grillner, S., LeBeau, F.E., Maex, R. & Markram, H. Synaptic pathways in neural microcircuits. Trends Neurosci. 28, 541551 (2005).
  30. Chaudhry, F.A. et al. The vesicular GABA transporter, VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABAergic neurons. J. Neurosci. 18, 97339750 (1998).
  31. Froemke, R.C., Merzenich, M.M. & Schreiner, C.E. A synaptic memory trace for cortical receptive field plasticity. Nature 450, 425429 (2007).
  32. Gandhi, S.P., Yanagawa, Y. & Stryker, M.P. Delayed plasticity of inhibitory neurons in developing visual cortex. Proc. Natl. Acad. Sci. USA 105, 1679716802 (2008).
  33. Markram, H. et al. Interneurons of the neocortical inhibitory system. Nat. Rev. Neurosci. 5, 793807 (2004).
  34. Buhl, E.H. et al. Effect, number and location of synapses made by single pyramidal cells onto aspiny interneurones of cat visual cortex. J. Physiol. (Lond.) 500, 689713 (1997).
  35. Kaiser, K.M., Lubke, J., Zilberter, Y. & Sakmann, B. Postsynaptic calcium influx at single synaptic contacts between pyramidal neurons and bitufted interneurons in layer 2/3 of rat neocortex is enhanced by backpropagating action potentials. J. Neurosci. 24, 13191329 (2004).
  36. Chklovskii, D.B., Mel, B.W. & Svoboda, K. Cortical rewiring and information storage. Nature 431, 782788 (2004).
  37. Stepanyants, A., Hof, P.R. & Chklovskii, D.B. Geometry and structural plasticity of synaptic connectivity. Neuron 34, 275288 (2002).
  38. Hendry, S.H., Fuchs, J., deBlas, A.L. & Jones, E.G. Distribution and plasticity of immunocytochemically localized GABAA receptors in adult monkey visual cortex. J. Neurosci. 10, 24382450 (1990).
  39. Hendry, S.H. et al. GABAA receptor subunit immunoreactivity in primate visual cortex: distribution in macaques and humans and regulation by visual input in adulthood. J. Neurosci. 14, 23832401 (1994).
  40. Hendry, S.H. & Jones, E.G. Reduction in number of immunostained GABAergic neurones in deprived-eye dominance columns of monkey area 17. Nature 320, 750753 (1986).
  41. Hendry, S.H. & Jones, E.G. Activity-dependent regulation of GABA expression in the visual cortex of adult monkeys. Neuron 1, 701712 (1988).
  42. Dan, Y. & Poo, M.M. Spike timing-dependent plasticity of neural circuits. Neuron 44, 2330 (2004).
  43. 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).
  44. Hensch, T.K. et al. Local GABA circuit control of experience-dependent plasticity in developing visual cortex. Science 282, 15041508 (1998).
  45. Huang, Z.J. et al. BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell 98, 739755 (1999).
  46. Kalatsky, V.A. & Stryker, M.P. New paradigm for optical imaging: temporally encoded maps of intrinsic signal. Neuron 38, 529545 (2003).
  47. Chattopadhyaya, B. et al. Experience and activity-dependent maturation of perisomatic GABAergic innervation in primary visual cortex during a postnatal critical period. J. Neurosci. 24, 95989611 (2004).
  48. Kubota, Y., Hatada, S.N. & Kawaguchi, Y. Important factors for the three-dimensional reconstruction of neuronal structures from serial ultrathin sections. Front. Neural Circuits 3, 110 (2009).
  49. De Paola, V. et al. Cell type-specific structural plasticity of axonal branches and boutons in the adult neocortex. Neuron 49, 861875 (2006).

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Author information

Affiliations

  1. Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Jerry L Chen,
    • Walter C Lin &
    • Elly Nedivi
  2. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Jerry L Chen &
    • Elly Nedivi
  3. Harvard-MIT Division of Health Science and Technology, Harvard Medical School, Cambridge, Massachusetts, USA.

    • Walter C Lin
  4. Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Jae Won Cha &
    • Peter T So
  5. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Peter T So
  6. Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo, Japan.

    • Yoshiyuki Kubota
  7. Division of Cerebral Circuitry, National Institute for Physiological Sciences, Okazaki, Japan.

    • Yoshiyuki Kubota
  8. Department of Physiological Science, Graduate University for Advanced Studies (SOKENDAI), Okazaki, Japan.

    • Yoshiyuki Kubota
  9. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Elly Nedivi

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