The defect, moreover, was confined to one of the two broad classes of synapses: excitatory, as opposed to inhibitory. "This selective change in the strength of one type of synapse, but not the other type, alters the balance between the two," said Sudhof.
Just as autistic or schizophrenic patients are in many respects normal, mice lacking the neurexin-1alpha gene were not grossly dysfunctional or survival-challenged. "The deletion didn't leave the mice unable to eat or to learn or to mate and procreate. If anything, they were actually better than the control mice at executing tasks requiring motor coordination," such as balancing atop a rotating rod without falling off, Sudhof said.
Importantly, though, the mutant mice exhibited discrete behavioral differences - repeated stereotypical behaviors such as self-grooming, impaired nest-building activity and so forth - suggestive of those associated with autism or schizophrenia, according to Sudhof.
Having demonstrated that the neurophysiological effects of neurexin-1alpha - a gene strongly implicated in autism and schizophrenia - correspond to behavioral abnormalities reminiscent of these cognitive disorders, Sudhof plans to use a new grant awarded by the National Institutes for Health to expand his search.
The NIH had put aside $60 million of its allocation as part of the economic stimulus package specifically for research on autism, and Sudhof's proposal was chosen amid heavy competition.
He and his colleagues in the Stanford Institute for Neuro-Innovation and Translational Neurosciences intend to use the grant to find out if other genes (such as those just identified in a study published in Nature on Oct. 7) affect the nervous system. The investigators will use established techniques to inactivate or increase the activity of 81 autism-associated genes in cultured mouse neurons, and then assess whether these changes affect neural development, synapse density and synapse function. If any of these effects are found, the gene modifications will be tested in whole mice.
Source: Stanford University Medical Center