Jacqueline N. Crawley, an internationally renowned behavioral neuroscientist, has received a five-year, nearly $3 million grant from the National Institutes of Health to understand the synaptic dysfunctions that limit how people with certain neurodevelopmental disorders form memories and learn. The research also will investigate the effectiveness of potential targeted therapies for the disorders: fragile X syndrome, Rett syndrome, Down syndrome and Angelman syndrome.
All of the conditions result in varying degrees of intellectual impairment and may cause physical disabilities. Fragile X syndrome also is the most widespread single-gene cause of autism. Rett syndrome is a disorder of the nervous system that affects mostly girls. Down syndrome and Angelman syndrome also affect cognition and have physical manifestations.
“Although fragile X, Rett, Down and Angelman syndromes do not share the same genetic signatures, they all are characterized by impaired synaptic plasticity and unusual shapes of their dendritic spines in neuronal synapses,” said Crawley, Robert E. Chason Endowed Chair in Translational Research, a researcher with the UC Davis MIND Institute and professor in the Department of Psychiatry and Behavioral Sciences.
“My collaborators and I hypothesize that the basic molecular defect responsible for these synaptic abnormalities and intellectual disabilities will be the same across these neurodevelopmental syndromes. We plan to test novel behavioral and pharmacological interventions that can be readily implemented clinically if they are proven to be safe and effective,” she said.
For memory and learning to occur, a complex sequence of molecular actions must take place to create new connections between neurons in the brain, Crawley explained. Upstream in the sequence are the mutated genes that alter the biological pathways crucial to the downstream development and strengthening of synapses, the small gaps between neurons that are fundamental to learning and memory.
A typical mature neuron has thousands of synapses through which it receives information from other neurons. Previous research has shown that learning and memory requires numerous complex connections between neurons. Each connection occurs through a synapse.
“We hypothesize that upstream genetic abnormalities undermine the actin stabilization that is fundamental to the internal cytoskeleton modifications which change the shapes of dendritic spines to appropriately form and stabilize new synapses,” Crawley said. “Failure of the actin cytoskeleton to properly reorganize is predicted to be a shared endpoint for intellectual disabilities of neurodevelopmental disorders.”
The study, “Convergent Synaptic Mechanisms in Neurodevelopmental Disorders,” will be conducted in mutant mouse models. It is funded by a $2.9 million grant from the National Institute of Neurological Disorders and Stroke. Crawley’s collaborators include Gary S. Lynch, professor of psychiatry and human behavior, and Christine M. Gall, professor of anatomy and neurobiology, both at UC Irvine.