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.
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health/National Institute of Mental Health grants R01 MH093725 and R01 MH101584 to JDB, R01 MH081935 and R01 DA017392 to PEC, F31 NS073200 and T32 GM007288 to MEK, the Seaver Foundation to HHN, the Human Frontier Science Program (HFSP) RGP0019/2015 to HHN, JDB and SW, Autism Speaks 8410 to JDB, and by the Israel Science Foundation (SFN) grant 1350/12 to SW. In addition, this study was supported by a generous gift from William G. Gibson and Paulina Rychenkova, PhD. We thank Dr. Mouna Maroun for her advice on the fear conditioning test, Dr. Jill Silverman for reviewing the manuscript, and Ms. Idil Ozturk, Ms. Ayesha Islam, and Ms. Deniz Bingul for their assistance in behavioral scoring. Funding Funder Grant reference number Author Human Frontier Science Program RGP0019/2015 Hala Harony-Nicolas Shlomo Wagner Joseph D Buxbaum National Institute of Mental Health F31-NS073200 Matthew E Klein National Institute of Mental Health T32-GM007288 Matthew E Klein National Institute of Mental Health R01-MH081935 Pablo E Castillo National Institute of Mental Health R01-DA17392 Pablo E Castillo Israel Science Foundation 1350/12 Shlomo Wagner National Institute of Mental Health R01-MH093725 Joseph D Buxbaum National Institute of Mental R01-MH101584 Joseph D Buxbaum The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
© Harony-Nicolas et al.
ASJC Scopus subject areas
- Neuroscience (all)
- Immunology and Microbiology (all)
- Biochemistry, Genetics and Molecular Biology (all)