The work also provides insights into the memory deficits and cognitive dysfunction in mentally retarded patients. Many of the genes tied to mental retardation regulate the way synapses are formed. Abnormal synapses apparently are responsible for the cognitive problems associated with mental retardation.

PAK (p21-activated kinase), a critical regulator of synaptic architecture, was inhibited in the mutant mice. In humans, the gene that encodes this enzyme is tied to mental retardation. "Overall, we believe that one of the underlying mechanisms for mental retardation is synaptic malformation that leads to cognitive dysfunction," Hayashi said. "One of the most significant findings of this study is that the structure of synapses links to the function of synapses, and the size of synapses reflect the strength of the synapse. The bigger the synapse, the more vesicles to carry more neurotransmitters and the more channel proteins to permeate and bind to the neurotransmitters."

In addition to Tonegawa, Hayashi and MIT research affiliate Hae-Yoon Jung, authors include Se-Young Choi, Hey-Kyoung Lee, Dawai Zhang and Alfredo Kirkwood at Johns Hopkins and B.S. Shankaranarayana Rao and Sumantra Chattarji in India.

This work is supported by the National Institutes of Health, Howard Hughes Medical Institute and RIKEN.

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