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

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.

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Figure 1: Chronic two-photon in vivo imaging of dendritic branch tip dynamics in superficial L2/3 cortical interneurons.
Figure 2: Monocular deprivation increases interneuron dendritic branch tip dynamics in adult binocular visual cortex.
Figure 3: Synapses are formed on newly extended branch tips.
Figure 4: Monocular deprivation induces laminar-specific dendritic arbor rearrangements.
Figure 5: Binocular deprivation specifically increases retractions of L2/3 branch tips.
Figure 6: Four days of monocular deprivation increases inhibitory synapse elimination onto L5 pyramidal apical dendrites.
Figure 7: Reduction in intracortical inhibition by fluoxetine treatment promotes experience-dependent branch tip remodeling.

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Acknowledgements

We thank J. Leslie, R. Schecter and J. Hoch for comments on the manuscript; M.F. Bear for helpful discussions; M. Kozberg for assistance in data analysis; J. Coleman, H.B. Yu, S. Horng and C. McCurry for assistance with optical intrinsic imaging; Y. Yamamoto (Yokohama Demonstration Laboratory, SII NanoTecnnology Inc.) for data collection assistance by Zeiss NVision40; S. Hatada and H. Kita (National Institute of Physiological Sciences) for serial electron microscopy reconstruction; and Y. Kawaguchi for valuable discussions regarding EM reconstructions. This work was sponsored by grants to E.N. from the US National Eye Institute (R01 EY017656) and from the Stanley Center for Psychiatric Research. J.L.C. was supported in part by the MIT-Portugal program. J.W.C. was supported in part by the Singapore-MIT Alliance-2 and Singapore-MIT Alliance for Research and Technology. Y.K. was supported by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (20500300, 22120518).

AUTHOR CONTRIBUTIONS

J.L.C. and E.N. designed monocular and binocular deprivation research studies; W.C.L. and E.N. designed fluoxetine research studies; Y.K. performed electron microscopy studies; J.L.C. and W.C.L. performed research and analyzed data; J.W.C. and P.T.S. contributed new reagents/analytic tools; J.L.C. and E.N. wrote the paper.

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The authors declare no competing financial interests.

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Chen, J., Lin, W., Cha, J. et al. Structural basis for the role of inhibition in facilitating adult brain plasticity. Nat Neurosci 14, 587–594 (2011). https://doi.org/10.1038/nn.2799

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