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

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

doi:10.21203/rs.3.rs-32445/v1

Cited by 4 publications

(4 citation statements)

References 60 publications

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“…For example, the neural circuits involving DAergic neurons in the VTA region play a fundamental role in social behavior (43). Consistently to our results, a significant decrease in the Th positive DAergic neurons, and an effective treatment with DA on the impaired social behavior was observed in an ASD model (44). Moreover, these results are of a translational significance.…”

Section: Discussionsupporting

confidence: 87%

A novel mutation in intron 1 of Wnt1 causes developmental loss of dopaminergic neurons in midbrain and ASD-like behaviors in rats

Tang

Yongyi²,

Zhu³

et al. 2023

Preprint

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Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with a strong genetic liability. Despite extensive studies, however, the underlying pathogenic mechanism still remains elusive. In the present study, we identified a homozygous mutation in the intron 1 of Wnt1 via large-scale screening of ASD risk/causative genes and verified that this mutation created a new splicing donor site in the intron1, and consequently, a loss of WNT1 expression. Interestingly, humanized rat models harboring this mutation exhibited robust ASD-like behaviors including impaired ultrasonic vocalization (USV), decreased social interactions, and restricted and repetitive behaviors. Moreover, in the substantia nigra compacta (SNpc) and the ventral tegmental area (VTA) of mutant rats, dopaminergic (DAergic) neurons were dramatically lost, together with a comparable decrease in striatal DAergic fibers. Furthermore, using single-cell RNA sequencing, we demonstrated that the decreased DAergic neurons in these midbrain areas might attribute to a shift of the boundary of the local pool of progenitor cells from the hypothalamic floor plate to the midbrain floor plate during the early embryonic stage. Moreover, treatments of mutant rats with levodopa could attenuate the impaired USV and social interactions almost completely, but not the restricted and repetitive behaviors. Our results for the first time documented that the developmental loss of DAergic neurons in the midbrain underlies the pathogenesis of ASD, and that the abnormal progenitor cell patterning is a cellular underpinning for this developmental DAergic neuronal loss. Importantly, the effective dopamine therapy suggests a translational significance in the treatment of ASD.

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Section: Discussionsupporting

confidence: 87%

A novel mutation in intron 1 of Wnt1 causes developmental loss of dopaminergic neurons in midbrain and ASD-like behaviors in rats

Tang

Yongyi²,

Zhu³

et al. 2023

Preprint

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“…Alterations in DA-mediated responses have also been reported in the BTBR mice (Squillace et al, 2014), a model for idiopathic autism, accompanied by decreased TH expression in several DA innervated brain regions (Chao et al, 2020). Interestingly, intranasal dopamine administration efficiently rescued the cognitive and social deficits of both BTBR and Fmr1 mutant ASD models (Chao et al, 2020), suggesting a causal role of DA deficiency in the behavioural phenotype of the mice.…”

Section: Discussionmentioning

confidence: 87%

Embryonic valproate exposure alters mesencephalic dopaminergic neurons distribution and septal dopaminergic gene expression in domestic chicks

Adiletta

Pross

Taricco

et al. 2021

Preprint

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In recent years, the role of the dopaminergic system in the regulation of social behavior is being progressively outlined, and dysfunctions of the dopaminergic system are increasingly associated with neurodevelopmental disorders, including ASD. To further elucidate the role of the dopaminergic system in ASD, we investigated the effects of embryonic exposure to valproic acid (VPA) on the postnatal development of the mesencephalic DA system in the domestic chick. We found that VPA affected the rostro-caudal distribution of DA neurons, without changing the expression levels of several dopaminergic markers in the mesencephalon. We also investigated a potential consequence of this altered DA neuronal distribution in the septum, a social brain area previously associated to social behaviour in several vertebrate species, describing alterations in the expression of genes linked to DA neurotransmission. These findings support the emerging hypothesis of a role of DA dysfunction in ASD pathogenesis. Together with previous studies showing impairments of early social orienting behaviour, these data also support the use of the domestic chick model to investigate the neurobiological mechanisms involved in early ASD symptoms.

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“…While a wide array of acute or short-term interventions rescue social interaction deficits in adult 75,97,[125][126][127][128][129][130][131][132][133][134]117,[135][136][137][138][139][140][118][119][120][121][122][123][124] and young [141][142][143][144][145][146] BTBR mice, very few probed their long-term efficacy. Pharmacological rescue interventions yielding long-term rescue of BTBR social deficits predominantly target mice up to the third postnatal week [147][148][149][150][151] , with effects lasting until adulthood.…”

Section: Discussionmentioning

confidence: 99%

Maturation of Nucleus Accumbens Synaptic Transmission Signals a Critical Period for the Rescue of Social Deficits in a Mouse Model of Autism Spectrum Disorder

Matthiesen

Khlaifia

Steininger

et al. 2023

Preprint

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Social behavior emerges early in development, a time marked by the onset of neurodevelopmental disorders featuring social deficits, including autism spectrum disorder (ASD). Although deficits in social interaction and communication are at the core of the clinical diagnosis of ASD, very little is known about their neural correlates at the time of clinical onset of the disorder. The nucleus accumbens (NAc), a brain region extensively implicated in social behavior, undergoes synaptic, cellular and molecular alterations in early life, and is particularly affected in ASD mouse models. To explore a link between the maturation of the NAc and neurodevelopmental deficits in social behavior, we compared age-dependent changes in spontaneous synaptic transmission in NAc shell medium spiny neurons (MSNs) between the highly social C57BL/6J mouse strain and the idiopathic ASD mouse model BTBR T+ Itpr3tf/J at postnatal day (P) 4, P6, P8, P12, P15, P21 and P30. We found that MSNs from both C57BL/6J and BTBR mice display age-dependent increases in spontaneous excitatory and inhibitory synaptic currents between P4 and P30. Comparison of NAc spontaneous transmission between strains showed that BTBR MSNs display increased excitatory transmission during the first postnatal week, and increased inhibition across the first, second and fourth postnatal weeks, suggesting accelerated maturation of excitatory and inhibitory synaptic inputs onto BTBR MSNs compared to C57BL/6J mice. These early life changes in synaptic transmission are consistent with a potential critical period in the maturation of the NAc, which could maximize the efficacy of interventions affecting social behavior. To test this possibility, we treated BTBR mice in either early life (P4-P8) or adulthood (P60-P64) with the mTORC1 antagonist rapamycin, a well-established rescue intervention for ASD-like behavior. We found that rapamycin treatment rescued social interaction deficits in BTBR mice when injected in infancy, but not in adulthood. These data emphasize the importance of studying brain regions involved in the pathophysiology of neurodevelopmental disorders at clinically-relevant time points, which may offer novel insight into the timing and targets of therapeutic interventions to maximize positive outcomes.

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

Cited by 4 publications

References 60 publications

A novel mutation in intron 1 of Wnt1 causes developmental loss of dopaminergic neurons in midbrain and ASD-like behaviors in rats

A novel mutation in intron 1 of Wnt1 causes developmental loss of dopaminergic neurons in midbrain and ASD-like behaviors in rats

Embryonic valproate exposure alters mesencephalic dopaminergic neurons distribution and septal dopaminergic gene expression in domestic chicks

Maturation of Nucleus Accumbens Synaptic Transmission Signals a Critical Period for the Rescue of Social Deficits in a Mouse Model of Autism Spectrum Disorder

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