Mouse to man: animal models and cell models in the study of Autism

Non-human model systems allow us to enhance our understanding of disease mechanisms in many disorders. These models provide an invaluable tool in identifying targets for drug and therapeutic development for human use. The use of rodents (e.g., mouse and rats) and stem cell models is widely disseminated throughout Autism research, but what discoveries have the use of these allowed and how have they led to therapeutic treatments?

Why use animal models?

In autism research, animal models provide a valuable tool to fill the gap in knowledge about altered brain mechanisms that lead to the manifestation of behavioral deficits characteristic of autism spectrum disorder (ASD).

Generation of animal models for ASD, relies on findings evolving from genetic and environmental studies, which inform us about the insults responsible for the ASD phenotype. Insults (e.g., genetic mutation) are mimicked in the species of choice to model the deficits we observe in individuals with ASD and to allow a methodical investigation of altered mechanisms at the molecular, cellular, and brain level.

© Rama

For example, studies in animal models can address questions about the biological effects of a specific genetic mutation on (1) the strength of interaction between nerve cells (known as synaptic plasticity), (2) the integrity of communication between brain regions that work together to regulate specific behavior (known as brain circuits) and (3) on cognitive, motor and social behaviors. Answers to these questions provide the platform for future studies focused on drug discovery and development

Animal models are also being used for testing translatable biomarkers, which are  measures that can be assessed comparably in both human and animal subjects. Once identified, these biomarkers can serve as tools to examine the efficacy of potential therapeutics in animal models, predict their effect in human subjects, and inform clinical trials.

Research at the Seaver Autism Center

At the Seaver Autism Center for Research, we are characterizing mouse and rat models with mutations in several ASD risk genes, including in the SHANK3, leading to Phelan McDermid Syndrome (PMS) and in the  FMR1 gene, leading to Fragile X syndrome. By taking the approach described above, we discovered that treatment with IGF-1 in a mouse model with a mutation in the Shank3 gene ameliorates synaptic plasticity and motor deficits.

These findings formed the basis of clinical trials with IGF-1 in individuals with PMS, which established the feasibility of IGF-1 treatment in PMS, providing proof of concept to advance knowledge about developing targeted treatments for the synaptic dysfunction associated with ASD.

Another example comes from our recent study on a rat model for ASD, the Shank3-deficient rat, which also harbors a mutation in the Shank3 gene. These rats exhibit social behavior and attentional deficits, recapitulating the neuropsychiatric features of PMS. The nature of the model’s deficits led us to test the effect of the pro-social hormone, oxytocin, on the synaptic plasticity and behavioral deficits.

We found oxytocin significantly improved social memory, attention, and synaptic plasticity deficits, suggesting that oxytocin may have therapeutic potential for  both social and non-social deficits in individuals with PMS, supporting our ongoing clinical trials with oxytocin in these individuals. At the Center, we are also using this model to develop electroencephalogram-based (EEG) biomarkers that we can employ in future studies to test the efficacy of novel therapeutics.

Stem Cells

The study of stem cells has also gained a lot of attention in autism research. Stem cells can be generated from blood or skin samples and be differentiated to nerve cells, which are examined in the lab.  Stem cells-derived nerve cells overcome the issue of limited access to living neurons, enable the identification of altereted molecular and cellular mechanisms, and allows for testing of drug effciancy at the individual level.

Stem cells are also efficient for carrying out high-throughput screening of small molecules, which can accelerate the discovery of new molecules with potential therapeutic effect. At the Seaver Center, we continue to develop the use of stem cells in autism research, and enroll every affected individual that visits our clinic, his/her parents, and when available, unaffected sibling in this research.

Tune into The Mount Sinai Hospital Facebook on the 5th of June at 11am EST / 3pm GMT to hear myself, Dr. Harony-Nicolas’s, speak in more depth about the topic of animal and cell models used in Autism research at the Seaver Center.

Learn more about the Seaver Autism Center at

Discover more of the current research ongoing in this field at Molecular Autism.

Dr. Hala Harony-Nicolas

Dr. Hala Harony-Nicolas is currently an Assistant Professor of Psychiatry at the Icahn School of Medicine at Mount Sinai. After completing her B.Sc, M.A, and Ph.D at the Israel Institute of Technology, she started her post-doctoral fellowship at The University of Haifa in 2008 and then at The Icahn School of Medicine at Mount Sinai in 2011. Her research interests include mechanisms underlying social behavior deficits, animal models for autism spectrum disorder and the oxytocin system in autism spectrum disorder. The research in Dr. Harony-Nicolas’s lab applies integrated molecular and behavioral neuroscience approaches and uses transgenic rat models for autism spectrum disorder and neurodevelopmental disorders to study the mechanisms underlying social behavior deficits, with a focus on the oxytocin system, known as a major modulator of mammalian social behavior, and on brain circuits of social behavior.

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