Postdoc Fellowship for Yi-Zhi Wang in support of: Explore ASD-related synaptic deficits in Drd1-positve MSN

Project: Research project

Description

Autism spectrum disorder (ASD) is a diverse group of neurodevelopmental disorders, which affects ~1.5% of American children with cognitive, motor, and emotional symptoms. There is no effective treatment for ASD due in part to a lack in our understanding of the pathological mechanism(s). Recently, oxytocin was reported as a promising treatment for ASD, which significantly improved anxiety, social skills and reduces repetitive behaviors. Nucleus accumbens (NAc) was found as the hub brain region which responses for these improvements. On the contrary, selectively removal of Neuroligin-3 from dopamine receptor 1 (Drd1) positive medium spiny neuron (MSN) in NAc, led to ASD-like repetitive behaviors. Therefore we hypothesized that synaptic malfunctions in NAc Drd1 (+) MSN lead to social deficits and repetitive behaviors in ASD. Our primary goal of this proposal is to explore the synaptic remodeling in NAc Drd1 (+) MSN after oxytocin treatment.
The proposal is based on the combination of Neuroligin-3 (Nlgn3) deletion mice and Drd1-Cre mice. In previous study, we successfully developed a set of tool kit to profile neuron type-specific synaptic proteomics in vivo. Our approach links proximity biotinylation, synaptic localization, cell specific expression (Cre-FLEx), Tandem Mass Tag (TMT) quantification, with shotgun proteomic analysis and machine learning. Postsynaptic targeted custom fusion proteins were cloned into FLEx adeno-associated viral (AAV) vectors with 2A-GFP. These AAV viruses are intracranially injected into the NAc of 12 Drd1-Cre::Nlgn3-/- mice. Then 6 mice will be treated with oxytocin and the other 6 will be treated with control vehicles. One month later, we will used behavior test to examine social skills and repetitive behaviors. Then we will compare the Drd1 (+) MSN synaptic proteomics between oxytocin group and control group in a systematic way. The most significant changed synaptic proteins after oxytocin treatment may sever as the hubs of synaptic malfunction in ASD.
Although NAc was reported as the ‘final locus’ for long term oxytocin treatment, there is a huge lack of knowledge that how oxytocin treatment improves the synaptic connectivity in NAc. Generally speaking, global administration of oxytocin is a lower efficient and perhaps, a risky way. It takes a long time and a high dose to lead to the ‘good change’ in NAc. Thus the patients may be exposed under the dangerous condition of side effects like subarachnoid hemorrhage and increased blood pressure. We plan to find the precise synaptic targets of oxytocin in NAc, which may provide novel targets for ASD therapeutic targets.
StatusActive
Effective start/end date1/15/191/14/21

Funding

  • Brain & Behavior Research Foundation (27793)

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Nucleus Accumbens
Oxytocin
Neurons
Proteomics
Therapeutics
Biotinylation
Autism Spectrum Disorder
yi-zhi
Dependovirus
Dopamine Receptors
Firearms
Subarachnoid Hemorrhage
Proteins
Anxiety
Blood Pressure
Control Groups
Brain