Systems Biology of Autism: The Case for the Caudate Nucleus

The concentrated efforts to discover genes implicated in causing autism via disruptions in neurodevelopment, or as explanations of autism as an ongoing chronic condition, have led to a long list of candidates. Many of these can be rationalized in terms of disturbed synaptic plasticity mechanisms. But this begs a larger question of where and in what circuits these altered synapses are to be found. A new generation of mouse models, into which candidate genes have been engineered, as well as advances in visualization and control using photonics, have revealed (somewhat surprisingly) that many of the synapses affected by these autism-related genes are in specific cell types. At our December 2011 Boston Club meeting, we considered specific effects on Purkinje cells within cerebellar circuits. We saw how these ‘local’ signaling differences gave rise to global behaviors in mice that could be related to autism. A similar situation is emerging for the basal ganglia. Autism-related genes (SAPAP and SHANK3), coding for post-synaptic scaffolding proteins, when mutated appear to affect the functioning of medium spiny neurons in the caudate nucleus in engineered mouse models. Presenters at this meeting ‘made the case’ for regarding cortical-basal ganglia circuits as a place to focus our attention in trying to explain why some persons with autism cannot speak, often have obsessive-compulsive tendencies, and have certain motor difficulties.

Matthew P. Anderson, M.D. Ph.D., Harvard Medical School

Margaret Bauman, MD, Harvard Medical School

Cortico-Striatal Circuit Dysfunction in Autism: Mechanisms and Potential Therapeutic Targets
Guoping Feng, Ph.D., Massachusetts Institute of Technology

The Surprising Deep Brain:  Striatum as a Hub in Neural Networks Implicated in Autism
Ann Graybiel, Ph.D., Massachusetts Institute of Technology

Martha Herbert, MD, Ph.D., Harvard Medical School

Ray Kelleher, MD, Ph.D., Harvard Medical School

Tal Kenet, Ph.D., Harvard Medical School

Dara Manoach, Ph.D., Harvard Medical School

Christopher J. McDougle, MD, Lurie Center for Autism, Massachusetts General Hospital

Wade Regehr, Ph.D., Harvard Medical School

Positive Feedback Loops Drive Postnatal Development
Bernardo Sabatini, MD, Ph.D., HMS Neurobiology

Mustafa Sahin, MD, Ph.D., Children’s Hospital Boston

Sam S-H Wang, Ph.D., Princeton University

Andrew W. Zimmerman, MD, Lurie Center for Autism, Massachusetts General Hospital

2012

The Nancy Lurie Marks Family Foundation, Wellesley, MA