A Dopamine Hypothesis of Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders characterized by social deficits and stereotyped behaviors. While several theories have emerged, the pathogenesis of ASD remains unknown. Although studies report dopamine signaling abnormalities in autistic patients, a coherent dopamine hypothesis which could link neurobiology to behavior in ASD is currently lacking. In this paper, we present such a hypothesis by proposing that autistic behavior arises from dysfunctions in the midbrain dopaminergic system. We hypothesize that a dysfunction of the mesocorticolimbic circuit leads to social deficits, while a dysfunction of the nigrostriatal circuit leads to stereotyped behaviors. Furthermore, we discuss 2 key predictions of our hypothesis, with emphasis on clinical and therapeutic aspects. First, we argue that dopaminergic dysfunctions in the same circuits should associate with autistic-like behavior in nonautistic subjects. Concerning this, we discuss the case of PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections) which displays behaviors similar to those of ASD, presumed to arise from dopaminergic dysfunctions. Second, we argue that providing dopamine modulators to autistic subjects should lead to a behavioral improvement. Regarding this, we present clinical studies of dopamine antagonists which seem to have improving effects on autistic behavior. Furthermore, we explore the means of testing our hypothesis by using neuroreceptor imaging, which could provide comprehensive evidence for dopamine signaling dysfunctions in autistic subjects. Lastly, we discuss the limitations of our hypothesis. Along these lines, we aim to provide a dopaminergic model of ASD which might lead to a better understanding of the ASD pathogenesis.

Behavioral changes and growth deficits in a CRISPR engineered mouse model of the schizophrenia-associated 3q29 deletion

“…Female and male B6.Del16 +/Bdh1-Tfrc mice showed attenuated sensitivity to amphetamine-induced locomotor activity at a high dose of drug, suggesting perturbations in the dopaminergic system and demonstrating a shared behavior phenotype. Disruptions in dopamine signaling have been shown to confer risk for both ASD and SZ (30,31). We also demonstrated that B6.Dlg1 +/mice did not share any of the behavioral phenotypes that are observed in B6.Del16 +/Bdh1-Tfrc mice.…”

Association between schizophrenia and autism spectrum disorder: A systematic review and meta‐analysis

“…Schizophrenia and ASD are reported to share some similar apparent [Cauda et al, ; Kocovska, Gaughran, Krivoy, & Meier, ; Lionel et al, ]. There is genetic, environmental, imaging, neurochemical, and inflammation evidence for a connection between schizophrenia and ASD [Cauda et al, ; Fiksinski et al, ; Kocovska et al, ; Pavăl, ; Prata, Santos, Almeida, Coelho, & Barbosa, ]. Recently, some scientists have focused on the association between schizophrenia and ASD [Abdallah et al, ; Bakken et al, ; Bradley, Summers, Wood, & Bryson, ; Fiksinski et al, ].…”

Dopaminergic Gene Dosage in Autism versus Developmental Delay: From Complex Networks to Machine Learning approaches

“…Research on putative causal aspects that conduct to the different manifestations of ASD remains a priority. The role of dopaminergic neurotransmission and its involvement in the causal pathway of ASD deserves attention in this regard (Ayano, 2016;Greene, Walsh, Mosner, & Dichter, 2018;Pavăl, 2017). For example, disruptions in the nigrostriatal pathway, classically linked to motor functions, has been proposed as a potential contributing cause of some motor repetitive behaviours in ASD whereas disturbances in the mesocorticolimbic pathway, involved in reward and cognitive related functions, may lead to social cognitive an affective impairments, (Fernández, Mollinedo-Gajate, & Peñagarikano, 2018;Supekar et al, 2018).…”