The Impact of the Williams Syndrome Mutations on Neural
Organization and Brain Function: A Window into Social Cognition

James S. McDonnell Foundation Collaborative Activity Award:
Bridging Brain, Mind and Behavior
January 1, 2002 -- January 1, 2005


Project 6: Molecular-genetic techniques for modulating brain regions and specific neuronal cell types related to human social cognition (Callaway and Amaral).


One of our Panel meetings involved the status on cloning techniques in the rhesus monkey. While exciting progress has been made (Wolf et al, 1999), it is clear that it will be some time before reliable genetic manipulations can be introduced into the nonhuman primate genome. We have therefore decided to exploit a recently established molecular-genetic technique currently under development in Dr. Callaway’s laboratory for introducing genetic materially focally into the primate brain. Focal lesions have been an important tool that has provided immense insight into the contributions of specific brain regions and systems to behavior. As described earlier, for example, amygdala lesions in adult primates (Emery et al., 2001) produce a hypersociability syndrome that is reminiscent of Williams syndrome. Permanent perturbations of one brain region, however, have the potential to influence the development and function of other structures throughout the brain. Long-term adaptations can be avoided by reversible inactivation of brain structures. It would also be desirable to target inactivation to particular cell types within complex neural tissues. Given the similarity in hypersociality of Williams subjects and adult monkeys with amygdala lesions, we have decided to initially direct this technique at the macaque monkey amygdala. As other brain regions are identified to be involved in social cognition, these techniques could also be used there as well. In fact, it will become possible to turn on or off selected brain regions either alone or in combination providing a powerful tool for analysis of the network of brain regions involved in social cognition.


The Callaway laboratory has developed molecular-genetic tools that allow cell type selective, quickly reversible neuronal inactivation in primates. These tools will be used initially to test the effects of amygdala inactivation on social behaviors. Briefly, adeno-associated virus (AAV) delivers transgenes into the amygdala. This virus allows stable integration and long term expression of genetic material. We will use the AAV to deliver the gene for the drosophila allatostatin receptor (AlstR). This receptor, when activated by its ligand (allatostatin), hyperpolarizes neurons and effectively silences them. Incorporation of cell type specific promoters into the virus will allow specific targeting of selected amygdala cell types. For example, it may be desirable to specifically inactivate excitatory neurons while leaving inhibitory circuits intact. Studies will initially be carried out by transiently inactivating the entire amygdala. But, as more knowledge is gained about which brains regions or cell types are most affected by the Williams deletion, more relevant inactivation probes can be produced. If, for example, the CYLN2, GTF2IRD1 and GTF2I genes were shown in Project 5 to be heavily and selectively expressed in the mature amygdala, it would be of interest to attempt to selectively modulate the neurons in which they are expressed. Of course, once we have developed this transient genetic lesioning technique, animals will undergo exhaustive evaluation of their social behaviors using the techniques that have been outlined in detail in Emery, et al (2001).


Thus, the specific aim of this project is to develop a more selective transient lesion tool. We will exploit the power of molecular biology to target specific neurons within certain brain regions that are particularly associated with social behavior.


Introduction Project 1 Project 2

Project 3

Project 4 Project 5 Project 6 Conclusion


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