Oxytocin improves behavioral and electrophysiological deficits in a novel Shank3-deficient rat.

Hala Harony-Nicolas,Shlomo Wagner,Nikolaos P Daskalakis,Mark G Baxter,Matthew E Klein,Pablo E Castillo,Matthew L Shapiro,Johann Du Hoffmann,Ozlem Bozdagi-Gunal,Sankalp Sonar,Mohammed Riad,Patrick R Hof,Joseph D Buxbaum,Maya Kay

doi:10.7554/elife.18904

Abstract

Mutations in the synaptic gene SHANK3 lead to a neurodevelopmental disorder known as Phelan-McDermid syndrome (PMS). PMS is a relatively common monogenic and highly penetrant cause of autism spectrum disorder (ASD) and intellectual disability (ID), and frequently presents with attention deficits. The underlying neurobiology of PMS is not fully known and pharmacological treatments for core symptoms do not exist. Here, we report the production and characterization of a Shank3-deficient rat model of PMS, with a genetic alteration similar to a human SHANK3 mutation. We show that Shank3-deficient rats exhibit impaired long-term social recognition memory and attention, and reduced synaptic plasticity in the hippocampal-medial prefrontal cortex pathway. These deficits were attenuated with oxytocin treatment. The effect of oxytocin on reversing non-social attention deficits is a particularly novel finding, and the results implicate an oxytocinergic contribution in this genetically defined subtype of ASD and ID, suggesting an individualized therapeutic approach for PMS.

Highlights

Phelan McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by intellectual disability (ID), absent or delayed speech, neonatal hypotonia, attention deficits and autism spectrum disorder (ASD)
We observed that the levels of the postsynaptic density (PSD) scaffolding protein Homer1 are decreased in the Shank3-deficient rats (Figure 1—figure supplement 1C), consistent with changes in the PSD and with well-replicated findings from Shank3-deficient mice
In our genetically modified rat model of PMS, we found that Shank3 deficiency impairs social memory and attention

Summary

Introduction

Phelan McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by intellectual disability (ID), absent or delayed speech, neonatal hypotonia, attention deficits and autism spectrum disorder (ASD). The neurobehavioral manifestations of PMS are caused by heterozygous mutations/ deletions in the SHANK3 gene leading to a reduced expression of the SHANK3 protein. Shank is a key structural component of the glutamatergic postsynaptic density (PSD), and interacts with glutamate receptors and cytoskeletal elements to regulate glutamate signaling and synaptic plasticity (Kreienkamp, 2008). It has been estimated that more than 80% of individuals with PMS meet ASD diagnostic criteria and that ~0.5–1% of ASD cases, 1–2% of ID cases, and up to 2% of cases with

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