Loss of Adenylyl Cyclase Type-5 in the Dorsal Striatum Produces Autistic-Like Behaviors

Hannah Kim, Yunjin Lee, Jin Young Park, Ji Eun Kim, Tae Kyung Kim, Juli Choi, Jung Eun Lee, Eun Hwa Lee, Daesoo Kim, Kyoung Shim Kim, Pyung Lim Han

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Autism spectrum disorders (ASDs) are a heterogeneous group of psychiatric illness characterized by common core symptoms including sociability deficits and stereotyped behaviors. ASD is caused by various genetic and non-genetic factors. The genetic effects of autism-related genes are usually global and are presented with multiple symptoms, which hamper understanding of the mechanism through which the diverse causes of ASD produce common symptoms. In the present study, we demonstrate that genetic or molecular disruption of an array of molecular networks centered on adenylyl cyclase type-5 (AC5 or ADCY5) in the dorsal striatum produces autistic-like behaviors. AC5 knockout (KO) mice exhibit increased repetitive behaviors and sociability deficits, the two core domains of ASD, and that siRNA-mediated suppression of AC5 within the dorsal striatum is sufficient to replicate these behavioral phenotypes. Notably, the autistic-like behaviors of AC5 KO mice are rescued by blocking mGluR5 glutamate receptors within the dorsal striatum. Furthermore, pharmacological or siRNA-mediated inhibition of mGluR3, GluA and GluN glutamate receptors in the dorsal striatum in wildtype mice also induces autistic-like behaviors. Optogenetic inhibition of the prelimbic cortical neurons projecting to the dorsal striatum in AC5 KO mice rescues the deficits in social and object novelty preferences. Our results suggest that AC5 mutation produces autistic-like symptoms through the upregulation of mGluR5 functions in the dorsal striatum and that the dorsal striatum regulated by AC5 is a neural correlate responsible for core ASD symptoms.

Original languageEnglish
Pages (from-to)7994-8008
Number of pages15
JournalMolecular Neurobiology
Volume54
Issue number10
DOIs
StatePublished - 1 Dec 2017

Keywords

  • Autism
  • Dorsal striatum
  • ERK
  • Glutamate receptors

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