Western University of Health Sciences researchers are studying a potential treatment for Angelman syndrome (AS), a neuro-genetic disorder that results in cognitive impairment, motor dysfunction, seizures and severe speech impediments.

The research, co-authored by College of Osteopathic Medicine of the Pacific Associate Professor of Physiology Xiaoning Bi, PhD, and Graduate College of Biomedical Sciences Dean Michel Baudry, PhD, examines the effectiveness of the Ampakine¿¥ CX929 on reducing the learning and memory impairments caused by Angelman syndrome.

The mechanism of the disease is a mutation or deletion of a gene that is maternally imprinted in the brain. A mouse model has been developed by the deletion of the maternal Ube3a gene. These AS mice exhibit several features of the human disease, including abnormal dendritic spine morphology and learning deficits. The animals also have a marked impairment of long-term potentiation and a defect in actin polymerization, Baudry said.

“When we treat these mice for five days, twice a day, with CX929, a generous gift from Cortex Pharmaceuticals Inc. (Irvine, Calif.), we improve all of these outward measurements – lack of actin polymerization, long-term potentiation, and impairment of learning and memory,” he said.

Ampakines are a class of drugs that modulate the effect of the neurotransmitter glutamate in the brain and were discovered and developed by co-author Gary Lynch at UC Irvine and licensed to Cortex Pharmaceuticals Inc.

AS mice have a reduced number of AMPA receptors on the synapse, Bi said. Ampakines can bolster activity of AMPA receptors.

“What is surprising and interesting is that the Ampakine compound not only enhances cognitive performance, but also increases the number of mature synapses,” Bi said.

Angelman syndrome is found in about one in 15,000 live births. Drs. Baudry and Bi attended an Angelman Syndrome Foundation meeting in Salt Lake City last year that brought together children with Angelman syndrome and their parents.

“All of these parents are very engaged and active in trying to find out the latest research findings,” Baudry said. “A lot of these children don’t talk, are in wheelchairs and cannot feed themselves. It’s a very devastating disease.”

Bi said the disease is not fatal. AS children can live to adulthood, but they need full-time care. This research is important to Angelman families, but the potential benefits extend beyond one disease.

“A number of developmental disorders which are associated with learning impairment – although they originate from different underlying mechanisms, different gene mutations – they still converge on a set of cellular mechanisms that are important for synaptic plasticity and learning and memory,” Baudry said. “This kind of treatment, because it acts at the end of this converging pathway, could indeed be useful to treat a variety of disorders that are characterized with learning impairment and autistic characteristics.”

The article was published in Neurobiology of Disease and is available online.

Baudry, M., et al., Ampakines promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman syndrome, Neurobiol. Dis. (2012), doi: 10.1016/j.nbd.2012.04.002