Dopaminergic Dysregulation in Syndromic Autism Spectrum Disorders: Insights From Genetic Mouse Models.

Polina Kosillo,Helen S Bateup

doi:10.3389/fncir.2021.700968

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by altered social interaction and communication, and repetitive, restricted, inflexible behaviors. Approximately 1.5-2% of the general population meet the diagnostic criteria for ASD and several brain regions including the cortex, amygdala, cerebellum and basal ganglia have been implicated in ASD pathophysiology. The midbrain dopamine system is an important modulator of cellular and synaptic function in multiple ASD-implicated brain regions via anatomically and functionally distinct dopaminergic projections. The dopamine hypothesis of ASD postulates that dysregulation of dopaminergic projection pathways could contribute to the behavioral manifestations of ASD, including altered reward value of social stimuli, changes in sensorimotor processing, and motor stereotypies. In this review, we examine the support for the idea that cell-autonomous changes in dopaminergic function are a core component of ASD pathophysiology. We discuss the human literature supporting the involvement of altered dopamine signaling in ASD including genetic, brain imaging and pharmacologic studies. We then focus on genetic mouse models of syndromic neurodevelopmental disorders in which single gene mutations lead to increased risk for ASD. We highlight studies that have directly examined dopamine neuron number, morphology, physiology, or output in these models. Overall, we find considerable support for the idea that the dopamine system may be dysregulated in syndromic ASDs; however, there does not appear to be a consistent signature and some models show increased dopaminergic function, while others have deficient dopamine signaling. We conclude that dopamine dysregulation is common in syndromic forms of ASD but that the specific changes may be unique to each genetic disorder and may not account for the full spectrum of ASD-related manifestations.

Highlights

Autism spectrum disorder (ASD) is a neurodevelopmental disorder primarily characterized by deficits in social interactions, as well as repetitive, restricted, and inflexible behaviors (American Psychiatric Association, 2013)
A particular question we aim to address is whether the wide diversity of genetic mouse models of ASD, with both constitutive and conditional mutations, show concordant changes in the function of midbrain DA neurons that may be causal for ASD-related behavioral changes
In the ventral striatum, optogenetic suppression of the VTAto-Nucleus Accumbens (NAc) pathway reduces sociability in mice, while activation increases social interactions via NAc D1 receptors (Gunaydin et al, 2014). These studies suggest possible sub-region differences in DA dynamics contributing to distinct aspects of ASD-associated behaviors: hyperdopaminergia in the dorsal striatum could cause persistent and spontaneous stereotypies, while hypodopaminergia in the nucleus accumbens could lead to reduced sociability

Summary

INTRODUCTION

Autism spectrum disorder (ASD) is a neurodevelopmental disorder primarily characterized by deficits in social interactions, as well as repetitive, restricted, and inflexible behaviors (American Psychiatric Association, 2013). In the ventral striatum, optogenetic suppression of the VTAto-Nucleus Accumbens (NAc) (mesolimbic) pathway reduces sociability in mice, while activation increases social interactions via NAc D1 receptors (Gunaydin et al, 2014) Together, these studies suggest possible sub-region differences in DA dynamics contributing to distinct aspects of ASD-associated behaviors: hyperdopaminergia in the dorsal striatum could cause persistent and spontaneous stereotypies, while hypodopaminergia in the nucleus accumbens could lead to reduced sociability. Using the same mouse model, another study in 3-4 month old male mice found no changes in midbrain DA neuron number or TH levels in dorsal or ventral striatum (Riday et al, 2012) Together, these data suggest a possible age-dependent decline in SNc DA neurons with loss-of-function of the maternal copy of Ube3a. This conclusion is further supported by the observation that Ube3am−/p+ mice have reduced behavioral

References expression and function

Findings

DISCUSSION