Article

Two distinct mechanisms for experience-dependent homeostasis

Received:
Accepted:
Published:

Abstract

Models of firing rate homeostasis such as synaptic scaling and the sliding synaptic plasticity modification threshold predict that decreasing neuronal activity (for example, by sensory deprivation) will enhance synaptic function. Manipulations of cortical activity during two forms of visual deprivation, dark exposure (DE) and binocular lid suture, revealed that, contrary to expectations, spontaneous firing in conjunction with loss of visual input is necessary to lower the threshold for Hebbian plasticity and increase miniature excitatory postsynaptic current (mEPSC) amplitude. Blocking activation of GluN2B receptors, which are upregulated by DE, also prevented the increase in mEPSC amplitude, suggesting that DE potentiates mEPSCs primarily through a Hebbian mechanism, not through synaptic scaling. Nevertheless, NMDA-receptor-independent changes in mEPSC amplitude consistent with synaptic scaling could be induced by extreme reductions of activity. Therefore, two distinct mechanisms operate within different ranges of neuronal activity to homeostatically regulate synaptic strength.

  • Subscribe to Nature Neuroscience for full access:

    $59

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

Additional information

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

References

  1. 1.

    Marder, E., O’Leary, T. & Shruti, S. Neuromodulation of circuits with variable parameters: single neurons and small circuits reveal principles of state-dependent and robust neuromodulation. Annu. Rev. Neurosci. 37, 329–346 (2014).

  2. 2.

    Davis, G. W. Homeostatic control of neural activity: from phenomenology to molecular design. Annu. Rev. Neurosci. 29, 307–323 (2006).

  3. 3.

    Turrigiano, G. G. The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135, 422–435 (2008).

  4. 4.

    Cooper, L. N. & Bear, M. F. The BCM theory of synapse modification at 30: interaction of theory with experiment. Nat. Rev. Neurosci. 13, 798–810 (2012).

  5. 5.

    Abraham, W. C. & Bear, M. F. Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci. 19, 126–130 (1996).

  6. 6.

    Abraham, W. C. Metaplasticity: tuning synapses and networks for plasticity. Nat. Rev. Neurosci. 9, 387–399 (2008).

  7. 7.

    Kirkwood, A., Rioult, M. C. & Bear, M. F. Experience-dependent modification of synaptic plasticity in visual cortex. Nature 381, 526–528 (1996).

  8. 8.

    Philpot, B. D., Espinosa, J. S. & Bear, M. F. Evidence for altered NMDA receptor function as a basis for metaplasticity in visual cortex. J. Neurosci. 23, 5583–5588 (2003).

  9. 9.

    Guo, Y. et al. Dark exposure extends the integration window for spike-timing-dependent plasticity. J. Neurosci. 32, 15027–15035 (2012).

  10. 10.

    Philpot, B. D., Sekhar, A. K., Shouval, H. Z. & Bear, M. F. Visual experience and deprivation bidirectionally modify the composition and function of NMDA receptors in visual cortex. Neuron 29, 157–169 (2001).

  11. 11.

    Chen, W. S. & Bear, M. F. Activity-dependent regulation of NR2B translation contributes to metaplasticity in mouse visual cortex. Neuropharmacology 52, 200–214 (2007).

  12. 12.

    He, H.-Y., Hodos, W. & Quinlan, E. M. Visual deprivation reactivates rapid ocular dominance plasticity in adult visual cortex. J. Neurosci. 26, 2951–2955 (2006).

  13. 13.

    Turrigiano, G. G., Leslie, K. R., Desai, N. S., Rutherford, L. C. & Nelson, S. B. Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature 391, 892–896 (1998).

  14. 14.

    Goel, A. & Lee, H. K. Persistence of experience-induced homeostatic synaptic plasticity through adulthood in superficial layers of mouse visual cortex. J. Neurosci. 27, 6692–6700 (2007).

  15. 15.

    He, K., Petrus, E., Gammon, N. & Lee, H.-K. Distinct sensory requirements for unimodal and cross-modal homeostatic synaptic plasticity. J. Neurosci. 32, 8469–8474 (2012).

  16. 16.

    Gao, M. et al. A specific requirement of Arc/Arg3.1 for visual experience-induced homeostatic synaptic plasticity in mouse primary visual cortex. J. Neurosci. 30, 7168–7178 (2010).

  17. 17.

    Goel, A. et al. Phosphorylation of AMPA receptors is required for sensory deprivation-induced homeostatic synaptic plasticity. PLoS One 6, e18264 (2011).

  18. 18.

    Desai, N. S., Cudmore, R. H., Nelson, S. B. & Turrigiano, G. G. Critical periods for experience-dependent synaptic scaling in visual cortex. Nat. Neurosci. 5, 783–789 (2002).

  19. 19.

    Hengen, K. B., Lambo, M. E., Van Hooser, S. D., Katz, D. B. & Turrigiano, G. G. Firing rate homeostasis in visual cortex of freely behaving rodents. Neuron 80, 335–342 (2013).

  20. 20.

    Keck, T. et al. Synaptic scaling and homeostatic plasticity in the mouse visual cortex in vivo. Neuron 80, 327–334 (2013).

  21. 21.

    Kotak, V. C. et al. Hearing loss raises excitability in the auditory cortex. J. Neurosci. 25, 3908–3918 (2005).

  22. 22.

    Glazewski, S., Greenhill, S. & Fox, K. Time-course and mechanisms of homeostatic plasticity in layers 2/3 and 5 of the barrel cortex. Philos. Trans. R. Soc. Lond. B Biol. Sci. 372, 20160150 (2017).

  23. 23.

    Greenhill, S. D., Ranson, A. & Fox, K. Hebbian and homeostatic plasticity mechanisms in regular spiking and intrinsic bursting cells of cortical layer 5. Neuron 88, 539–552 (2015).

  24. 24.

    Fong, M. F., Newman, J. P., Potter, S. M. & Wenner, P. Upward synaptic scaling is dependent on neurotransmission rather than spiking. Nat. Commun. 6, 6339 (2015).

  25. 25.

    Barnes, S. J. et al. Deprivation-induced homeostatic spine scaling in vivo is localized to dendritic branches that have undergone recent spine loss. Neuron 96, 871–882.e5 (2017).

  26. 26.

    Gianfranceschi, L. et al. Visual cortex is rescued from the effects of dark rearing by overexpression of BDNF. Proc. Natl Acad. Sci. USA 100, 12486–12491 (2003).

  27. 27.

    Benevento, L. A., Bakkum, B. W., Port, J. D. & Cohen, R. S. The effects of dark-rearing on the electrophysiology of the rat visual cortex. Brain Res. 572, 198–207 (1992).

  28. 28.

    Gu, Y. et al. Neuregulin-dependent regulation of fast-spiking interneuron excitability controls the timing of the critical period. J. Neurosci. 36, 10285–10295 (2016).

  29. 29.

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

  30. 30.

    Huang, S., Hokenson, K., Bandyopadhyay, S., Russek, S. J. & Kirkwood, A. Brief dark exposure reduces tonic inhibition in visual cortex. J. Neurosci. 35, 15916–15920 (2015).

  31. 31.

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

  32. 32.

    Gu, Y. et al. Obligatory role for the immediate early gene NARP in critical period plasticity. Neuron 79, 335–346 (2013).

  33. 33.

    Greenblatt, D. J. & Sethy, V. H. Benzodiazepine concentrations in brain directly reflect receptor occupancy: studies of diazepam, lorazepam, and oxazepam. Psychopharmacology (Berl.) 102, 373–378 (1990).

  34. 34.

    Rittenhouse, C. D. et al. Stimulus for rapid ocular dominance plasticity in visual cortex. J. Neurophysiol. 95, 2947–2950 (2006).

  35. 35.

    Rittenhouse, C. D., Shouval, H. Z., Paradiso, M. A. & Bear, M. F. Monocular deprivation induces homosynaptic long-term depression in visual cortex. Nature 397, 347–350 (1999).

  36. 36.

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

  37. 37.

    Christian, C. A. et al. Endogenous positive allosteric modulation of GABAA receptors by diazepam binding inhibitor. Neuron 78, 1063–1074 (2013).

  38. 38.

    Wen, L. et al. Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc. Natl Acad. Sci. USA 107, 1211–1216 (2010).

  39. 39.

    Cho, K. K. A., Khibnik, L., Philpot, B. D. & Bear, M. F. The ratio of NR2A/B NMDA receptor subunits determines the qualities of ocular dominance plasticity in visual cortex. Proc. Natl Acad. Sci. USA 106, 5377–5382 (2009).

  40. 40.

    Drasbek, K. R. & Jensen, K. THIP, a hypnotic and antinociceptive drug, enhances an extrasynaptic GABAA receptor-mediated conductance in mouse neocortex. Cereb. Cortex 16, 1134–1141 (2006).

  41. 41.

    Sun, Y. et al. Neuregulin-1/ErbB4 signaling regulates visual cortical plasticity. Neuron 92, 160–173 (2016).

  42. 42.

    Pratt, K. G. & Aizenman, C. D. Homeostatic regulation of intrinsic excitability and synaptic transmission in a developing visual circuit. J. Neurosci. 27, 8268–8277 (2007).

  43. 43.

    Gambrill, A. C., Storey, G. P. & Barria, A. Dynamic regulation of NMDA receptor transmission. J. Neurophysiol. 105, 162–171 (2011).

  44. 44.

    Lee, K. F. H., Soares, C. & Béïque, J.-C. Tuning into diversity of homeostatic synaptic plasticity. Neuropharmacology 78, 31–37 (2014).

  45. 45.

    Petrus, E. et al. Vision loss shifts the balance of feedforward and intracortical circuits in opposite directions in mouse primary auditory and visual cortices. J. Neurosci. 35, 8790–8801 (2015).

  46. 46.

    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).

  47. 47.

    Ranson, A., Cheetham, C. E. J., 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).

  48. 48.

    Deeg, K. E. & Aizenman, C. D. Sensory modality-specific homeostatic plasticity in the developing optic tectum. Nat. Neurosci. 14, 548–550 (2011).

  49. 49.

    Frémaux, N. & Gerstner, W. Neuromodulated spike-timing-dependent plasticity, and theory of three-factor learning rules. Front. Neural Circuits 9, 85 (2016).

  50. 50.

    Zenke, F., Agnes, E. J. & Gerstner, W. Diverse synaptic plasticity mechanisms orchestrated to form and retrieve memories in spiking neural networks. Nat. Commun. 6, 6922 (2015).

  51. 51.

    Tallaksen-Greene, S. J., Janiszewska, A., Benton, K., Ruprecht, L. & Albin, R. L. Lack of efficacy of NMDA receptor-NR2B selective antagonists in the R6/2 model of Huntington disease. Exp. Neurol. 225, 402–407 (2010).

  52. 52.

    Rumbaugh, G. & Vicini, S. Distinct synaptic and extrasynaptic NMDA receptors in developing cerebellar granule neurons. J. Neurosci. 19, 10603–10610 (1999).

  53. 53.

    Murase, S. et al. Matrix metalloproteinase-9 regulates neuronal circuit development and excitability. Mol. Neurobiol. 53, 3477–3493 (2016).

  54. 54.

    Niell, C. M. & Stryker, M. P. Highly selective receptive fields in mouse visual cortex. J. Neurosci. 28, 7520–7536 (2008).

  55. 55.

    Chen, L., Deng, Y., Luo, W., Wang, Z. & Zeng, S. Detection of bursts in neuronal spike trains by the mean inter-spike interval method. Prog. Nat. Sci. 19, 229–235 (2009).

Download references

Acknowledgements

Research reported in this article was supported by the National Eye Institute of the National Institutes of Health under award number R01EY012124 (to A.K.), R01EY016431 (to E.Q.), R01EY025922 (to E.Q., A.K. and H.-K. L.) and R01-EY014882 (to H.-K.L.). A.K. was also supported by NIH grant P01 AG009973. M.C.D.B. was supported by grants T32EY007143 and T32HL110952.

Author information

Author notes

    • Michelle C. D. Bridi
    • , Roberto de Pasquale
    •  & Crystal L. Lantz

    These authors contributed equally to this work.

  1. These authors contributed equally: Michelle C. D. Bridi, Roberto de Pasquale and Crystal L. Lantz.

Affiliations

  1. Mind/Brain Institute, Johns Hopkins University, Baltimore, MD, USA

    • Michelle C. D. Bridi
    • , Roberto de Pasquale
    • , Se-Young Choi
    • , Kaiwen He
    • , Trinh Tran
    • , Su Z. Hong
    • , Andrew Dykman
    • , Hey-Kyoung Lee
    •  & Alfredo Kirkwood
  2. Department of Biology, University of Maryland, College Park, MD, USA

    • Crystal L. Lantz
    •  & Elizabeth M. Quinlan
  3. Neuroscience and Cognitive Sciences Program, University of Maryland, College Park, MD, USA

    • Yu Gu
    • , Andrew Borrell
    •  & Elizabeth M. Quinlan
  4. Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USA

    • Hey-Kyoung Lee
    •  & Alfredo Kirkwood

Authors

  1. Search for Michelle C. D. Bridi in:

  2. Search for Roberto de Pasquale in:

  3. Search for Crystal L. Lantz in:

  4. Search for Yu Gu in:

  5. Search for Andrew Borrell in:

  6. Search for Se-Young Choi in:

  7. Search for Kaiwen He in:

  8. Search for Trinh Tran in:

  9. Search for Su Z. Hong in:

  10. Search for Andrew Dykman in:

  11. Search for Hey-Kyoung Lee in:

  12. Search for Elizabeth M. Quinlan in:

  13. Search for Alfredo Kirkwood in:

Contributions

M.C.D.B., R.d.P., T.T., K.H. and S.Z.H. collected slice electrophysiology data. M.C.D.B. and R.d.P. analyzed slice electrophysiology data. S.-Y.C. provided initial data for the inception of the project. C.L.L., Y.G. and A.B. collected and analyzed the in vivo unit recording data. A.D. and H.-K.L. provided code for analysis of single-unit firing properties. M.C.D.B., E.M.Q. and A.K. wrote the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Elizabeth M. Quinlan or Alfredo Kirkwood.

Integrated supplementary information

  1. Supplementary Figure 1 Single-unit recordings in awake, head-fixed animals.

    (A,B) Representative waveforms from units recorded before and after DE (A) and BS (B) (see Figure 1A, D). Thin lines represent individual waveforms; black lines represent the average waveform. (C) Single unit firing rates in naïve mice at baseline and following DE with diazepam treatment. There was no significant difference between groups (P=0.676, 2-tailed Wilcoxon rank sum test), confirming that diazepam prevents the DE-mediated increase in spontaneous firing (see Figure 1A). Data are shown as individual points; dashed lines and error bars represent mean±SEM. Sample size is indicated in parentheses as (cells, mice)

  2. Supplementary Figure 2 Effects of visual deprivation and modulation of inhibition on single-unit firing properties.

    (A) Spontaneous bursting increased after DE and after BS with flumazenil treatment. *P≤0.001 (U(60)=211.0), #P=0.047 (U(60)=235.0), †P=0.006 (U(64)=328.0), ‡P=0.013 (U(49)=193.0), 2-tailed Wilcoxon rank sum test. Sample size is shown as (units, mice). (B) Non-burst firing rates increased after DE. *P≤0.001 (U(60)=235.0), 2-tailed Wilcoxon rank sum test. No significant differences were observed between the recovery and DE+diazepam (U(60)=363.0, P=0.100), baseline and BS (U(64)=403.0, P=0.071), or recovery and BS+flumazenil (U(49)=238, P=0.103) conditions. Sample size as shown in panel (A). Data are shown as individual points; dashed lines and error bars represent mean±SEM. (C) Raster plots of two example units from awake, head-fixed mice viewing a grey screen. Spikes were classified as non-burst (blue) or part of a burst (magenta) (see Methods). A portion of the raster plots is enlarged (below) to show more detail

  3. Supplementary Figure 3 Effects of acute drug treatment on spontaneous single-unit firing properties.

    (A) Single unit recordings were obtained during presentation of a grey screen in awake, head-fixed mice. V1 firing rates were measured at baseline (open circles) and 20 minutes after drug administration i.p. (filled circles). Diazepam and THIP decreased, and flumazenil increased, spontaneous firing rate. *P≤0.001, #P=0.002, 2-tailed Wilcoxon signed rank test. Vehicle injection did not alter spontaneous firing rate (Z(15)=0.646, P=0.528). Sample size is indicated as (units, mice). (B) To demonstrate the long-lasting effects of a single drug injection i.p., single unit recordings were made from V1 under isoflurane anesthesia. Diazepam decreased and flumazenil increased (4 units, 4 mice per group) spontaneous neuronal firing rates for at least 2h after the injection. The dotted gray line indicates baseline firing rate for reference. *P≤0.001 vs. −30 minute time point, One-way repeated measures ANOVA with Holm-Sidak post-hoc test. Sample size is shown as (units, mice). (C,D) Single unit firing properties during acute drug administration. Diazepam and THIP decreased, and flumazenil increased, both spontaneous bursting (C; 2-tailed paired t test) and the inter-burst firing rate (D, 2-tailed Wilcoxon signed rank test). *P≤0.001, #P=0.002. Vehicle injection did not alter these parameters (bursting, 2-tailed paired t test t(15)=−0.313, P=0.759; inter-burst firing rate, 2-tailed Wilcoxon signed rank test Z(15)=0.267, P=0.831. Sample size as shown in (A). For all panels, individual unit firing parameters at each time point are connected by grey lines. Colored symbols and lines indicate the mean and error bars represent SEM

  4. Supplementary Figure 4 Diazepam administered i.c.v. prevents the DE-mediated increase in mEPSC amplitude.

    (A) Average mEPSC traces after diazepam or vehicle infusion directly into the lateral ventricle via osmotic minipump during DE. (B) mEPSC amplitude was larger in vehicle- than diazepam-infused animals. *P=0.013, 2-tailed t test. Dashed lines and error bars indicate mean±SEM. For clarity, some data points are displaced horizontally. Sample size is shown as (cells, mice)

  5. Supplementary Figure 5 Activation of Gi-DREADD in PV cells elevates spontaneous activity in neighboring regular-spiking neurons.

    (A) CNO (5 mg/kg i.p.) increased the firing rate of regular spiking neurons in hemispheres where Gi-DREADD was expressed in PV cells. *P≤0.001, 2-tailed paired t test. Data are from 31 units recorded from 3 awake, head-fixed animals viewing a grey screen. Grey lines represent individual units before and after CNO administration; green line and error bars represent mean ±SEM. (B) For mEPSC recordings (Fig. 3C, D), patch electrodes were targeted to pyramidal cells neighboring mCherry-labeled, Gi-DREADD expressing PV cells

  6. Supplementary Figure 6 Diazepam administered i.c.v. prevents the DE-mediated increase in GluN2B function.

    (A) DE increased the percentage of NMDAR EPSC blocked by ifenprodil (*P=0.021, 2-tailed t test) and the NMDA receptor decay constant (τw) (†P=0.002, 2-tailed t test) in animals with no drug administration. (B) In DE animals, diazepam prevented the GluN2B increase compared to vehicle (*P=0.039; †P=0.030; 2-tailed t test). Solid lines: average baseline NMDAR current; dashed lines: after ifenprodil wash-in. Traces are normalized to baseline. Data are displayed as individual points; dashed lines indicate average (±SEM); sample size is shown as (neurons, mice)

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–6 and Supplementary Tables 1–5

  2. Reporting Summary