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Early hyperactivity and precocious maturation of corticostriatal circuits in Shank3B−/− mice

Nature Neuroscience volume 19, pages 716724 (2016) | Download Citation

Abstract

Some autistic individuals exhibit abnormal development of the caudate nucleus and associative cortical areas, suggesting potential dysfunction of cortico-basal ganglia (BG) circuits. Using optogenetic and electrophysiological approaches in mice, we identified a narrow postnatal period that is characterized by extensive glutamatergic synaptogenesis in striatal spiny projection neurons (SPNs) and a concomitant increase in corticostriatal circuit activity. SPNs during early development have high intrinsic excitability and respond strongly to cortical afferents despite sparse excitatory inputs. As a result, striatum and corticostriatal connectivity are highly sensitive to acute and chronic changes in cortical activity, suggesting that early imbalances in cortical function alter BG development. Indeed, a mouse model of autism with deletions in Shank3 (Shank3B−/−) shows early cortical hyperactivity, which triggers increased SPN excitatory synapse and corticostriatal hyperconnectivity. These results indicate that there is a tight functional coupling between cortex and striatum during early postnatal development and suggest a potential common circuit dysfunction that is caused by cortical hyperactivity.

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Acknowledgements

We thank I. Oldenburg for help with in vivo recordings and analysis and J. Levasseur and R. Pemberton for mouse genotyping and colony management. We thank S. da Silva, C. Deister and the members of the Sabatini laboratory for helpful discussions and critical reading of the manuscript. R.T.P. was supported by the Alice and Joseph Brooks fellowship and the Nancy Lurie Marks clinical and research fellowship in autism. Y.K. was supported by the Leonard and Isabelle Goldenson Research Fellowship and the Nancy Lurie Marks Family Foundation. This work was supported by the National Institute of Neurological Disorders and Stroke (NS046579, to B.L.S.) and the Nancy Lurie Marks Foundation.

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  1. Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA.

    • Rui T Peixoto
    • , Wengang Wang
    • , Donyell M Croney
    • , Yevgenia Kozorovitskiy
    •  & Bernardo L Sabatini

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Contributions

R.T.P. and B.L.S. conceived the study and wrote the manuscript. R.T.P. carried out in vivo recordings and analyzed the data. R.T.P., W.W. and Y.K. carried out in vitro slice recordings and R.T.P. analyzed the data. D.M.C. performed the behavioral experiments and dendritic spine imaging and analysis.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Bernardo L Sabatini.

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DOI

https://doi.org/10.1038/nn.4260

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