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Recurrent network activity drives striatal synaptogenesis

A Corrigendum to this article was published on 25 July 2012

Abstract

Neural activity during development critically shapes postnatal wiring of the mammalian brain. This is best illustrated by the sensory systems, in which the patterned feed-forward excitation provided by sensory organs and experience drives the formation of mature topographic circuits capable of extracting specific features of sensory stimuli1,2. In contrast, little is known about the role of early activity in the development of the basal ganglia, a phylogenetically ancient group of nuclei fundamentally important for complex motor action and reward-based learning3,4. These nuclei lack direct sensory input and are only loosely topographically organized5,6, forming interlocking feed-forward and feed-back inhibitory circuits without laminar structure. Here we use transgenic mice and viral gene transfer methods to modulate neurotransmitter release and neuronal activity in vivo in the developing striatum. We find that the balance of activity between the two inhibitory and antagonist pathways in the striatum regulates excitatory innervation of the basal ganglia during development. These effects indicate that the propagation of activity through a multi-stage network regulates the wiring of the basal ganglia, revealing an important role of positive feedback in driving network maturation.

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Figure 1: Conditional knockout of Slc32a1 from direct or indirect pathway MSNs abolishes GABAergic output.
Figure 2: Conditional knockout of Slc32a1 in direct and indirect pathway MSNs results in opposing changes to excitatory synapse number.
Figure 3: In vivo , developmentally restricted postnatal manipulation of activity in direct and indirect pathway MSNs results in opposing changes to excitatory synapse number.
Figure 4: Corticostriatal activity drives synaptogenesis in MSNs.

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Acknowledgements

We thank Sabatini laboratory members for comments on the manuscript; B. Roth, K. Deisseroth and M. During for AAV backbones encoding hM4D, ChR2 and Cre, respectively; and C. Gerfen for the Rbp4-Cre mouse line. Confocal imaging was done through the Harvard NeuroDiscovery and Olympus Imaging Centers. This work was supported by grants from NINDS (NS046579, B.L.S); the W.F. Milton Fund Award and the Leonard and Isabelle Goldenson Research Fellowship (Y.K.); and NIH (F31 NS074842) and Shapiro predoctoral fellowship (A.S.).

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Authors

Contributions

Y.K., A.S. and B.L.S. designed the experiments. Y.K. and A.S. performed experiments and analysed data. C.A.J. assisted in experiments and genotyping. B.B.L. generated the conditional Slc32a1 mouse. Y.K., A.S. and B.L.S. wrote the paper with contributions from C.A.J. and B.B.L.

Corresponding author

Correspondence to Bernardo L. Sabatini.

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The authors declare no competing financial interests.

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Kozorovitskiy, Y., Saunders, A., Johnson, C. et al. Recurrent network activity drives striatal synaptogenesis. Nature 485, 646–650 (2012). https://doi.org/10.1038/nature11052

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