Dissecting the circuits underlying autism-like behaviors in mice
Guoping Feng, Ph.D.
Massachusetts Institute of Technology
Many genes implicated in autism encode proteins at synapses, the connections between neurons. These proteins include the neuroligin-neurexin complex and the PSD95-SAPAP-SHANK complex at synapses that release the neurotransmitter glutamate1.
SHANK3 is a scaffolding protein that plays a key role in the assembly and function of synapses containing glutamate, a chemical messenger that mediates excitatory signals. Disruption of SHANK3 is thought to be the cause of the core neurodevelopmental and neurobehavioral deficits in Phelan-McDermid syndrome, an autism-related disorder2. SHANK3 mutations have also emerged as a potential monogenic cause of autism3.
To investigate the function of SHANK3 at synapses and to elucidate how its disruption may lead to autism, Guoping Feng and his colleagues at the Massachusetts Institute of Technology generated mice lacking SHANK3. This disruption of SHANK3 results in both structural and functional changes in cortico-striatal synapses, which are part of the neural circuits strongly implicated in autism.
Feng discovered that cortico-striatal synaptic dysfunction in the mice leads to an imbalance in activity between the direct and indirect pathways in the basal ganglia circuit in the brain. This circuit plays an important role in controlling motor and behavioral output. The fine-tuning of these two pathways is critical for basal ganglia function, and imbalance may be a key mechanism underlying repetitive behaviors5.
Together, these data demonstrate a critical role for SHANK3 in cortico-striatal synaptic structure and function, and provide a potential circuitry mechanism for autism-related behaviors in mice lacking SHANK3.
1. Ting J.T. et al. Ann. Rev. Neurosci. 35, 49-71 (2012) PubMed
2. Phelan K. and H.E. McDermid Mol. Syndromol. 2, 186-201 (2012) PubMed
3. Peça J. and G. Feng Curr. Opin. Neurobiol. 22, 866-872 (2012) PubMed
4. Peça J. et al. Nature 472, 437-442 (2011) PubMed
5. Wang W. et al. (2013) SHANK3 deletion leads to striatal indirect pathway-specific synaptic plasticity deficits. Manuscript submitted for publication.
Award #: 178130