Journal Article

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

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

2017

Overview

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. Phelan-McDermid syndrome is a genetic disorder on the autism spectrum that affects how children develop in several ways, with additional symptoms including attention deficits, delays in learning to speak and motor problems. This syndrome is known to be caused by changes in a single gene known as SHANK3 that disrupt communication between brain cells involved in memory and learning. However, we do not know how these changes relate to the symptoms of Phelan-McDermid syndrome. To understand how genetic changes affect the human brain, researchers often carry out experiments in rats or other small rodents because they have brains that are similar to ours. Harony-Nicolas et al. genetically modified rats to carry changes in the SHANK3 gene that reflect those found in people with Phelan-McDermid syndrome. The rats had disabilities related to those seen in Phelan-McDermid syndrome, including limits in long-term social memory and reduced attention span. They also showed changes in the connections between important parts of the brain. Therefore, studying these rats could help us to understand the link between molecular and cellular changes in the brain and how they affect people with Phelan-McDermid syndrome, and associated symptoms. Previous studies have shown that a chemical called oxytocin, which is naturally produced by the brain, helps to form bonds between individuals and can cause positive feelings in relation to certain memories. Harony-Nicolas et al. found treating the rats with oxytocin boosted social memory and led to improvements in other symptoms of Phelan-McDermid syndrome. In particular, oxytocin treatment helped to increase the attention span of the rats. Rats with changes in the SHANK3 gene will be a useful tool for future research into Phelan-McDermid syndrome, particularly in understanding how it affects the connections between brain cells, leading to the symptoms of Phelan-McDermid syndrome. A future challenge will be to find out whether oxytocin has the potential to be developed into a therapy to treat Phelan-McDermid syndrome in humans. Since there is evidence that SHANK3 is involved in other forms of autism, these rats will also be useful in understanding the other ways in which autism can develop.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Amino acids / Animals / attention / Autism / autism spectrum disorder / Behavior / Behavior, Animal - drug effects / Behavioral plasticity / Chromosome Deletion / Chromosome Disorders - drug therapy / Chromosome Disorders - pathology / Chromosome Disorders - physiopathology / Chromosomes, Human, Pair 22 / Disease Models, Animal / Drug therapy / Gene mutations / Genetic aspects / Health aspects / Hippocampal plasticity / Hippocampus / Hippocampus - pathology / Immunoglobulins / Intellectual disabilities / Medicine / Mutation / Nerve Tissue Proteins - deficiency / Nervous system / Neurobiology / Neurodevelopmental disorders / Neuroscience / Neurosciences / Oxytocin / Oxytocin - administration & dosage / Phelan McDermid Syndrome / Prefrontal cortex / Prefrontal Cortex - pathology / Proteins / Rats / Rodents / Shank3 / Social Behavior / Social interactions / Synaptic plasticity