Abnormal Striatal Development Underlies the Early Onset of Behavioral Deficits in Shank3B Mice.
Rui Tiago Peixoto, Lynne Chantranupong, Richard Hakim, James Levasseur, Wengang Wang, Tasha Merchant, Kelly Gorman, Bogdan Budnik, Bernardo Luis Sabatini
Author Information
Rui Tiago Peixoto: 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.
Lynne Chantranupong: Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA.
Richard Hakim: Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA.
James Levasseur: Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA.
Wengang Wang: Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA.
Tasha Merchant: 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.
Kelly Gorman: Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA.
Bogdan Budnik: Mass Spectrometry and Proteomic Laboratory, FAS Division of Science, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
Bernardo Luis Sabatini: Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA.
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 Shank3BMice 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 Shank3BMice 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.
