Targeting inhibitory cerebellar circuitry to alleviate behavioral deficits in a mouse model for studying idiopathic autism

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 + Itpr3 tf /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.

Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism

“…We also found that BTBR mice display cognitive and emotional abnormalities akin to the psychiatric comorbidity of ASD [16,17]. In addition, similar neuroanatomical changes between the BTBR model and ASD subpopulations are reported [18,19].…”

Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism

“…The BTBR strain is a phenotypic model for idiopathic ASD, which exhibits impaired sociability, altered ultrasonic vocalization and increased self-grooming behaviors, simulating the main symptoms of human ASD [15]. We also found that BTBR mice display cognitive and emotional abnormalities akin to the psychiatric comorbidity of ASD [16,17]. In addition, similar neuroanatomical changes between the BTBR model and ASD subpopulations are reported [18,19].…”

“…Because of their respective deficit in social approaching or social novelty [16,33], in the three-chamber test, BTBR mice received DA before the habituation trial, whereas Fmr1-KO mice received DA before the sociability trial. As BTBR mice have intact recognition of social novelty [16,17], the social novelty trial was excluded here to avoid excessive administration of DA in the same subjects within a short time. The dosage and timing of DA administration were based on a previous study in mice [34] .…”

“…BTBR mice (n = 12; 8 males and 4 females) were tested using a within-subject design to minimize individual differences. Choice of sex was based on our earlier report that both male and female BTBR mice show autistic-like behaviors [17]. Half of the animals were treated with DA and the other half with vehicle.…”

“…Otherwise, n represented the number of mice per group. Sample sizes were determined on the basis of previous studies using similar experimental protocols [16,17,33].…”