Striatal inhibition of MeCP2 or TSC1 produces sociability deficits and repetitive behaviors

Yunjin Lee, Hannah Kim, Pyung Lim Han

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Autism spectrum disorder (ASD) is a heterogeneous group of neurobehavioral disorders characterized by the two core domains of behavioral deficits, including sociability deficits and stereotyped repetitive behaviors. It is not clear whether the core symptoms of ASD are produced by dysfunction of the overall neural network of the brain or that of a limited brain region. Recent studies reported that excessive glutamatergic or dopaminergic inputs in the dorsal striatum induced sociability deficits and repetitive behaviors. These findings suggest that the dorsal striatum plays a crucial role in autistic-like behaviors. The present study addresses whether functional deficits of well-known ASD-related genes in the dorsal striatum also produce ASD core symptoms. This study also examines whether these behavioral changes can be modulated by rebalancing glutamate and/or dopamine receptor activity in the dorsal striatum. First, we found that the siRNA-mediated inhibition of Shank3, Nlgn3, Fmr1, Mecp2, or Tsc1 in the dorsal striatum produced mild to severe behavioral changes in sociability, cognition, and/or repetitive behaviors. The knockdown effects of Mecp2 and Tsc1 on behavioral changes were the most prominent. Next, we demonstrated that behavioral changes induced by striatal inhibition of MeCP2 and TSC1 were rescued by D-cycloserine (an NMDA agonist), fenobam (an mGluR5 antagonist), SCH23390 (a D1 antagonist), and/or ecopipam (a D1 partial antagonist), pharmacological drugs that are known to regulate ASD-like symptoms in animal models. Collectively, these results suggest that the dorsal striatum is a critical brain region that, when dysfunctional, produces the core symptoms of ASD.

Original languageEnglish
Pages (from-to)539-549
Number of pages11
JournalExperimental Neurobiology
Volume27
Issue number6
DOIs
StatePublished - Dec 2018

Keywords

  • Autism spectrum disorder
  • Dorsal striatum
  • MeCP2
  • TSC1

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