Striatal increase of dopamine receptor 2 density in idiopathic and syndromic mouse models of autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) comprises a wide range of neurodevelopmental phenotypes united by impaired social interaction and repetitive behavior. Environmental and genetic factors are associated with the pathogenesis of ASD, while other cases are classified as idiopathic. The dopaminergic system has a profound impact in the modulation of motor and reward-motivated behaviors, and defects in dopaminergic circuits are implicated in ASD. In our study, we compare three well-established mouse models of ASD, one idiopathic, the BTBR strain, and two syndromic, Fmr1 and Shank3 mutants. In these models, and in humans with ASD, alterations in dopaminergic metabolism and neurotransmission were highlighted. Still, accurate knowledge about the distribution of dopamine receptor densities in the basal ganglia is lacking. Using receptor autoradiography, we describe the neuroanatomical distribution of D1 and D2 receptors in dorsal and ventral striatum at late infancy and adulthood in the above-mentioned models. We show that D1 receptor binding density is different among the models irrespective of the region. A significant convergence in increased D2 receptor binding density in the ventral striatum at adulthood becomes apparent in BTBR and Shank3 lines, and a similar trend was observed in the Fmr1 line. Altogether, our results confirm the involvement of the dopaminergic system, showing defined alterations in dopamine receptor binding density in three well-established ASD lines, which may provide a plausible explanation to some of the prevalent traits of ASD. Moreover, our study provides a neuroanatomical framework to explain the utilization of D2-acting drugs such as Risperidone and Aripiprazole in ASD.

Lotusine ameliorates propionic acid‐induced autism spectrum disorder‐like behavior in mice by activating D1 dopamine receptor in medial prefrontal cortex

“…However, in vitro studies indicated that PPA treatment reduced the DRD1 protein level in PC12 cells. This observed inconsistency may be attributed to different expressions of DRD1 in different ASD models (Chhabra et al, 2023; Homberg et al, 2016; Lee et al, 2018) and the potential of lotusine to target other proteins to promote DRD1 expression, such as fragile X mental retardation protein (FMRP) (Wang et al, 2008), which warrants further investigation.…”

The cortico-striatal circuitry in autism-spectrum disorders: a balancing act

“…Gene variants associated with dopaminergic markers and receptors have been identified in ASD ( De Krom et al, 2009 ; Staal et al, 2012 ; Gangi et al, 2016 ; Mariggiò et al, 2021 ). Several ASD animal models show increased gene expression of dopamine D2 receptors in iMSNs ( Maisterrena et al, 2022 Chhabra et al, 2023 ; reviewed in Gandhi and Lee, 2021 ). Increased striatal levels of dopamine D2 receptors was documented in Rett syndrome ( Chiron et al, 1993 ) and more recently, increased striatal D2 receptor gene expression has been reported in ASD post-mortem brains ( Brandenburg et al, 2020 ).…”