Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental disorders characterized by social and communication deficits, repetitive behavior, and rigid thinking patterns (American Psychiatric Association, 2013). Around one percent of children worldwide are diagnosed with ASD, typically displaying symptoms around 12 to 18 months of age (Zeidan et al., 2022). Although ASD diagnosis is mainly based on clinical evaluations of behavior in humans, numerous rodent models have been employed to study ASD because of their well-characterized autistic-like behavioral deficits. For example, some mice with mutations in the MECP2 gene are used to study Rett syndrome, other mice with mutations in the FMR1 gene are used to study Fragile X syndrome, and mice with mutations in the Shank3 gene are used to study Phelan-McDermid syndrome, all mutations of which are associated with ASD (Bey & Jiang, 2014). Shank3 is a prominent autism candidate gene that encodes a postsynaptic density scaffold protein that regulates synaptic development, and disrupting Shank3 expression in mice has been shown to result in synaptic defects, abnormal social interaction and communication, and repetitive behaviors (Wang et al., 2011). Since Shank3 mutations contribute to approximately one percent of ASD cases and induce autistic-like deficits, Mei et al. (2016) demonstrated that restoring Shank3 expression during adulthood can selectively rescue some autistic-like behavioral deficits, which points to continued neural plasticity in the adult brain that mediates the effects of post-developmental Shank3 re-expression.
To carry out this study, the researchers generated a novel Shank3 conditional knock-in mouse model using a tamoxifen-induced, CreER-mediated genetic construct targeting the functional domain of the Shank3 gene. This model achieves temporal control of Shank3 expression, whereby Shank3 is expressed only after tamoxifen administration. As such, the researchers carried out their experiments using three groups of mice: wild-type mice expressing Shank3 and treated with tamoxifen (control), Shank3-knockout mice treated with tamoxifen (Shank3 restoration), and Shank3-knockout mice treated with corn oil vehicle (no restoration). They first found that adult Shank3 re-expression restores spontaneous excitatory activity, dendritic spine density, and synaptic levels of important postsynaptic density scaffold proteins and glutamate receptor subunits in striatal neurons, which are involved in motor planning (Mei et al., 2016). These results highlight the ability of Shank3 to alter dendritic spine formation and neuronal firing patterns without restriction to a critical period in development.
After demonstrating rescued striatal neurotransmission and spine formation, the researchers set out to explore the effect of adult Shank3 expression on autistic-like behavioral abnormalities. Compared to wild-type mice, Shank3-knockout mice typically display increased repetitive grooming, reduced social interaction with strangers (measured using a modified three-chamber assay), reduced exploratory behavior (measured by total distance traveled in an open-field test), increased anxiety-like behavior (measured by time spent in the open arm of an elevated zero maze test), and increased motor coordination deficits (measured by faster fall times in a rotarod test). The researchers showed that adult restoration of Shank3 significantly reduces grooming time and increases social preference for strangers, similar to wild-type mice. However, adult Shank3 re-expression does not rescue exploratory behavior, anxiety-like behavior, or motor coordination (Mei et al., 2016). A possible explanation for the selective nature of these rescued behavioral abnormalities is that the neural circuit mechanisms of anxiety and motor coordination involve a greater degree of connectivity with other brain regions that do not display the continued plasticity shown in the striatum. Indeed, after treating juvenile mice with tamoxifen within the first three weeks of postnatal development rather than during adulthood, the researchers were able to reduce anxiety-like behavior and motor coordination deficits in the Shank3-re-expressed mice compared to the Shank3-knockout mice (Mei et al., 2016). These results point to the presence of a critical period in development during which irreversible autistic-like behavioral abnormalities in adults can be rescued.
Taken altogether, the results of this study highlight the ability to selectively rescue autistic-like deficits during adulthood, but they also point to a critical period in development that can be targeted by early-life interventions. The work of Mei et al. (2016) provides a foundation for future autism research to focus on characterizing cortico-striatal circuit development and dynamic connectivity patterns within these circuits. This line of work also sets the stage for extensive research into critical periods of development, which grant researchers a window of opportunity to target synaptic transmission defects and behavioral deficits associated with ASD.
About the Author Mohammed Abuelem is a senior at Harvard College concentrating in Neuroscience with a secondary in Global Health and Health Policy.
References
American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders Fifth Edition. Arlington, VA: American Psychiatric Association
Bey, A. L. & Jiang, Y. H. (2014). Overview of Mouse Models of Autism Spectrum Disorders. Current Protocols in Pharmacology, 66, 5.66.1-5.66.26. doi:10.1002/0471141755.ph0566s66
Mei, Y., Monteiro, P., Zhou, Y., Kim, J. A., Gao, X., Fu, Z., & Feng, G. (2016). Adult Restoration of Shank3 Expression Rescues Selective Autistic-like Phenotypes. Nature, 530, 481- 484. doi:10.1038/nature16971
Wang, X., McCoy, P. A., Rodriguiz, R. M., Pan, Y., Je, H. S., Roberts, A. C., ... Jiang, Y. H. (2011). Synaptic Dysfunction and Abnormal Behaviors in Mice Lacking Major Isoforms of Shank3. Human Molecular Genetics, 20(15), 3093-3108. https://doi.org/10.1093/hmg/ddr212
Zeidan, J., Fombonne, E., Scorah, J., Ibrahim, A., Durkin, M. S., Saxena, S., … Elsabbagh, M. (2022). Global Prevalence of Autism: A Systematic Review Update. Autism Research, 15(5), 778-790. https://doi.org/10.1002/aur.2696