title: Loss of Adenylyl Cyclase Type-5 in the Dorsal Striatum Produces Autistic-Like Behaviors.
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.
authors.affiliation: Department of Brain and Cognitive Sciences, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul, 120-750, Republic of Korea.
authors.forename: Hannah
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Brain and Cognitive Sciences, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul, 120-750, Republic of Korea.
authors.forename: Yunjin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Brain and Cognitive Sciences, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul, 120-750, Republic of Korea.
authors.forename: Jin-Young
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Brain and Cognitive Sciences, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul, 120-750, Republic of Korea.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Brain and Cognitive Sciences, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul, 120-750, Republic of Korea.
authors.forename: Tae-Kyung
authors.initials: TK
authors.lastname: Kim
authors.affiliation: Department of Brain and Cognitive Sciences, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul, 120-750, Republic of Korea.
authors.forename: Juli
authors.initials: J
authors.lastname: Choi
authors.affiliation: Department of Brain and Cognitive Sciences, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul, 120-750, Republic of Korea.
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Department of Brain and Cognitive Sciences, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul, 120-750, Republic of Korea.
authors.forename: Eun-Hwa
authors.initials: EH
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Daesoo
authors.initials: D
authors.lastname: Kim
authors.affiliation: Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.|University of Science and Technology, Daejeon, 305-806, Republic of Korea.
authors.forename: Kyoung-Shim
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Brain and Cognitive Sciences, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul, 120-750, Republic of Korea. plhan@ewha.ac.kr.|Department of Chemistry and Nano Science, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul, 120-750, Republic of Korea. plhan@ewha.ac.kr.
authors.forename: Pyung-Lim
authors.initials: PL
authors.lastname: Han
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001321:Autistic Disorder / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D009154:Mutation / Q000235:genetics*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D013239:Stereotyped Behavior / Q000502:physiology
chemical_list: D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V
keywords: Autism; Dorsal striatum; ERK; Glutamate receptors