Abnormal Striatal Development Underlies the Early Onset of Behavioral Deficits in Shank3B -/- Mice.

Autor:	Peixoto RT; Department of Psychiatry, University of Pittsburgh, 450 Technology Dr, Pittsburgh, PA 15219, USA; Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA. Electronic address: rup14@pitt.edu., Chantranupong L; Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA., Hakim R; Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA., Levasseur J; Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA., Wang W; Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA., Merchant T; Department of Psychiatry, University of Pittsburgh, 450 Technology Dr, Pittsburgh, PA 15219, USA; Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA., Gorman K; Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA., Budnik B; Mass Spectrometry and Proteomic Laboratory, FAS Division of Science, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA., Sabatini BL; Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2019 Nov 12; Vol. 29 (7), pp. 2016-2027.e4.
DOI:	10.1016/j.celrep.2019.10.021
Abstrakt:	The neural substrates and pathophysiological mechanisms underlying the onset of cognitive and motor deficits in autism spectrum disorders (ASDs) remain unclear. Mutations in ASD-associated SHANK3 in mice (Shank3B -/- ) result in the accelerated maturation of corticostriatal circuits during the second and third postnatal weeks. Here, we show that during this period, there is extensive remodeling of the striatal synaptic proteome and a developmental switch in glutamatergic synaptic plasticity induced by cortical hyperactivity in striatal spiny projection neurons (SPNs). Behavioral abnormalities in Shank3B -/- mice emerge during this stage and are ameliorated by normalizing excitatory synapse connectivity in medial striatal regions by the downregulation of PKA activity. These results suggest that the abnormal postnatal development of striatal circuits is implicated in the onset of behavioral deficits in Shank3B -/- mice and that modulation of postsynaptic PKA activity can be used to regulate corticostriatal drive in developing SPNs of mouse models of ASDs and other neurodevelopmental disorders. (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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