30905
Implication of the Oxytocin System in Shank3-Deficiency
Social deficits are a core symptom of autism spectrum disorder (ASD). To date, behavioral therapies are the first line of intervention for treating impaired social behaviors, whereas pharmacological treatments have been ineffective at addressing this symptom domain. To inform treatment targets, there is an urgent need to understand the pathophysiology underlying social deficits. The hypothalamic oxytocin system is a key modulator of social behavior that is well conserved across species. Despite the wealth of behavioral and pharmacological studies implicating oxytocin in social behavior, and the increased interest in oxytocin as a therapeutic in ASD, little is known about the effect of ASD-associated mutations, such as SHANK3, on the oxytocin system. Moreover, it is unclear whether impairments in the oxytocin system underlie social deficits in some forms of ASD. We have recently demonstrated attentional, social recognition memory, and synaptic plasticity deficits in a rat model carrying a Shank3 mutation: the Shank3-deficient rat. We showed that both behavioral and synaptic plasticity deficits in this model are reversed by oxytocin. In this project, we study the effect of a Shank3 mutation on the neural oxytocin system.
Objectives:
The objectives of our study are to understand if a Shank3 mutation imposes a deleterious effect on (1) the hypothalamic oxytocin system in the paraventricular nucleus where oxytocin is produced and released and (2) the social recognition memory circuit that comprises brain regions targeted by the paraventricular nucleus. Further, we aim to examine the causality between alterations in the oxytocin system and the social recognition memory deficits that we have reported in the Shank3-deficient rat model.
Methods:
We are leveraging the Shank3-deficient rat model to explore the effect of the Shank3 mutation on the neural oxytocin circuitry. Techniques include: immunohistochemistry to study the effect of the Shank3 mutation on the morphology of oxytocin neurons, brain microdialysis to assess oxytocin levels during social behavior, fiber photometry to record neural activity of oxytocin neurons during social interaction, and chemogenetic tools to manipulate the oxytocin neural population in vivo and test the causality between social behavior deficits and alterations in the oxytocin system in Shank3-deficient rats.
Results:
Our preliminary findings show increased oxytocin immunoreactivity in oxytocin neurons within the paraventricular nucleus of Shank3-deficient rats, suggesting an accumulation of the oxytocin peptide due to impaired secretion. Furthermore, we observe diminished photometry signals in the PVN during social interaction, suggesting impaired neural activity of PVN neurons.
Conclusions:
Our findings suggest that Shank3 mutations impact the oxytocin system by altering neural activity of oxytocin neurons and the release and oxytocin. These variations may underlie the social recognition memory deficits that we have previously reported in the Shank3-deficient rat model.