Targeting inhibitory cerebellar circuitry to alleviate behavioral deficits in a mouse model for studying idiopathic autism
Journal
Neuropsychopharmacology
Series/Report No.
Neuropsychopharmacology
Journal Volume
45
Journal Issue
7
Start Page
1159-1170
ISSN
0893-133X
1740-634X
Date Issued
2020-03-16
Author(s)
Marron Fernandez de Velasco, Ezequiel
Pathak, Salil Saurav
Maitra, Swati
Zhang, Hao
Duvick, Lisa
Wickman, Kevin
Orr, Harry T.
Hirai, Hirokazu
Yang, Yi-Mei
Abstract
Autism spectrum disorder (ASD) encompasses wide-ranging neuropsychiatric symptoms with unclear etiology. Although the cerebellum is a key region implicated in ASD, it remains elusive how the cerebellar circuitry is altered and whether the cerebellum can serve as a therapeutic target to rectify the phenotype of idiopathic ASD with polygenic abnormalities. Using a syndromic ASD model, e.g., Black and Tan BRachyury T+Itpr3tf/J (BTBR) mice, we revealed that increased excitability of presynaptic interneurons (INs) and decreased intrinsic excitability of postsynaptic Purkinje neurons (PNs) resulted in low PN firing rates in the cerebellum. Knowing that downregulation of Kv1.2 potassium channel in the IN nerve terminals likely augmented their excitability and GABA release, we applied a positive Kv1.2 modulator to mitigate the presynaptic over-inhibition and social impairment of BTBR mice. Selective restoration of the PN activity by a new chemogenetic approach alleviated core ASD-like behaviors of the BTBR strain. These findings highlight complex mechanisms converging onto the cerebellar dysfunction in the phenotypic model and provide effective strategies for potential therapies of ASD.
Subjects
Animals
Autism Spectrum Disorder
Autistic Disorder
Cerebellum
Disease Models
Animal
Male
Mice
Inbred C57BL
SDGs
Publisher
Springer Science and Business Media LLC
Type
journal article