Oxytocin Reverses Social Deficits in the Shank3-Deficient Rat, a First Genetically Modified Rat Model for Autism
Shank3 is a scaffolding protein that forms a key structural part of the postsynaptic density (PSD) of excitatory synapses, where it recruits glutamate receptors and binds cytoskeletal elements regulating glutamate signaling. Haploinsufficiency of SHANK3 causes a monogenic form of autism spectrum disorder (ASD), known as Phelan McDermid Syndrome (PMS). The findings emerging form independent mouse models with Shank3 mutations together with our recent findings in a novel rat model with a Shank3 mutation, provided evidence for impaired glutamatergic synaptic function in ASD-associated brain regions and deficits in several behavioral measures related to ASD. Yet the neurobiology of Shank3-deficiency is not fully known and no treatments are available to target the core symptoms of PMS. Oxytocin is well known for its pro-social effect, however its efficacy in PMS has not been studied yet.
Objectives: The first aim of our study is to uncover the synaptic plasticity-related mechanisms affected in Shank3 deficient rats, which may underlie the synaptic and behavioral deficits that are evidenced in Shank3-deficiency. Our second aim is to study the capability of candidate compounds to reverse the core symptoms observed in PMS. To achieve aim one, we are using unbiased transcriptomic and proteomic analysis to compare WT and Shank3-deficient rats. For aim two, we are studying the efficacy of different candidate compounds, including oxytocin, in reversing the synaptic plasticity and social behavioral deficits that we observed in the Shank3-deficient rat model.
Proteomic and transcriptomic analysis: To compare the mRNA and protein expression profiles between the Shank3-deficient rats and their WT littermate, we used RNA sequencing (RNAseq) technology and 2-dimensional differential in-gel electrophoresis, respectively, then projected the transcpritional-perturbed signatures onto human brain co-expression network from different developmental periods and applied gene ontology (GO) analysis to reveal the affected molecular pathways. Pharmacological treatment: We treated the Shank3-deficient rats with intracerebroventricular injections of saline or the neuropeptide oxytocin and then tested their long-term social recognition memory (SRM). Behavior: We have previously reported that the long-term SRM of the Shank3-deficient rats is impaired. To test the effect of oxytocin and other compound on social behavior we test the long-term SRM of the rats using the social discrimination test, following oxytocin or Saline injection. Electrophysiological recording: We have previously reported the hippocampal long-term potentiation (LTP) in the Shank3-deficient rats is impaired. To study the effect of oxytocin on LTP, we use in vitro recording from acute hippocampal brain slices following perfusion in oxytocin bath.
Proteomic and transcriptomic approaches followed by bioinformatics analysis of brain co-expression networks demonstrated that decreased Shank3 levels influence molecular networks implicated in distinct developmental periods, mainly during fetal developmental periods, and indicated that Shank3 may play an important role in scaffolding the synaptic proteins involved in the actin remodeling machinery. Finally, the application of the neuropeptide oxytocin reversed the deficits in both social behavior and hippocampal synaptic function.
The results suggest that, although clinical studies of oxytocin in autism remain quite equivocal, oxytocin has a therapeutic potential for PMS.
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