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

Owen Y Chao,Jay-Shake Li,Yi-Mei Yang,Joseph P Huston,Susanne Nikolaus,Claudia Mattern,Salil S Pathak,Hao Zhang,Nathan Dunaway

doi:10.1186/s13041-020-00649-7

Abstract

The dopamine (DA) system has a profound impact on reward-motivated behavior and is critically involved in neurodevelopmental disorders, such as autism spectrum disorder (ASD). Although DA defects are found in autistic patients, it is not well defined how the DA pathways are altered in ASD and whether DA can be utilized as a potential therapeutic agent for ASD. To this end, we employed a phenotypic and a genetic ASD model, i.e., Black and Tan BRachyury T+Itpr3tf/J (BTBR) mice and Fragile X Mental Retardation 1 knockout (Fmr1-KO) mice, respectively. Immunostaining of tyrosine hydroxylase (TH) to mark dopaminergic neurons revealed an overall reduction in the TH expression in the substantia nigra, ventral tegmental area and dorsal striatum of BTBR mice, as compared to C57BL/6 J wild-type ones. In contrast, Fmr1-KO animals did not show such an alteration but displayed abnormal morphology of TH-positive axons in the striatum with higher “complexity” and lower “texture”. Both strains exhibited decreased expression of striatal dopamine transporter (DAT) and increased spatial coupling between vesicular glutamate transporter 1 (VGLUT1, a label for glutamatergic terminals) and TH signals, while GABAergic neurons quantified by glutamic acid decarboxylase 67 (GAD67) remained intact. Intranasal administration of DA rescued the deficits in non-selective attention, object-based attention and social approaching of BTBR mice, likely by enhancing the level of TH in the striatum. Application of intranasal DA to Fmr1-KO animals alleviated their impairment of social novelty, in association with reduced striatal TH protein. These results suggest that although the DA system is modified differently in the two ASD models, intranasal treatment with DA effectively rectifies their behavioral phenotypes, which may present a promising therapy for diverse types of ASD.

Highlights

Autism spectrum disorder (ASD) is a prevailing neurodevelopmental disorder, primarily diagnosed by a core of symptoms including social impairments, communication difficulties, restricted interests and repetitive behaviors [1]
Differential alterations of the DA system in Black and Tan BRachyury T+Itpr3tf/J (BTBR) and Fragile X Mental Retardation 1 knockout (Fmr1-KO) mice To investigate whether and how the DA pathways are modified in the ASD models, we labelled dopaminergic neurons with an anti-tyrosine hydroxylase (TH) antibody in brain sections taken from age, sex- and background matched wild type (WT), BTBR and Fmr1-KO mice
We first examined the origins of the DA system, i.e. the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) in the midbrain, and their major projections to the dorsal striatum and nucleus accumbens (NAc) via the respective nigrostriatal and mesocorticolimbic pathways [4]

Summary

Introduction

Autism spectrum disorder (ASD) is a prevailing neurodevelopmental disorder, primarily diagnosed by a core of symptoms including social impairments, communication difficulties, restricted interests and repetitive behaviors [1]. A system-level analysis of brain transcriptome has pointed out that the patterns of gene expression in schizophrenia, bipolar disorder and ASD significantly overlap, and that neurons/synapses are susceptible targets of polygenic modulations in all cases [3]. Projections from VTA to the nucleus accumbens (NAc) and the frontal cortex make up the mesocorticolimbic pathway to regulate memory, reward, motivation and emotion [4]. Similar to ADHD [5], bipolar disorder [6] and schizophrenia [7], DA dysfunction is linked to ASD [8]. The STR and the frontal cortex that receive dopaminergic inputs are altered in human ASD [9,10,11] as well as in animal models with autistic-like behaviors induced by environmental factors [12]. Drugs involved in DA actions, such as risperidone, clozapine, haloperidol and methylphenidate, have yielded beneficial effects in ASD patients [14], none of them acts selectively on the DA system

Methods

Results

Conclusion