Establishing the basic principles of effective intervention for difficult behavior in Angelman Syndrome

Dr. Chris Oliver, University of Birmingham
Edgbaston, Birmingham, United Kingdom

What are some of the motivating and reinforcing events that might be used to help children and adults with AS change behaviors?  Funding from ASF to Dr. Oliver helps answer such questions. His work has been instrumental in identifying pro-social behaviors and other activities that can be used as rewards and reinforcements to improve problematic behaviors in AS, such as pinching and other types of aggressive or self injurious behaviors. Work from this grant was conducted in the United Kingdom under rigorous programs of behavioral design and control and has clearly pointed out how those with AS have unique behaviors different from those with other types of genetic syndromes associated with intellectual deficiency.


Are the neurological symptoms of Angelman Syndrome reversible? An inducible mouse model for Angelman Syndrome

Dr. Ype Elgersma, Erasmus University Medical Center Ratterdam
Rotterdam, Netherlands

This grant to Dr. Elgersma and his colleagues, built further upon his earlier significant work demonstrating that many of the neurological and behavioral features of the Angelman mouse model could be reversed by changing the phosphorylation status of an important enzyme located near the neuronal synapse, CAMKII. This project funded a bold effort to establish a new Angelman mouse model that would enable the UBE3A gene to be turned on after an Angelman mouse is born. This research strategy is to learn to what extent the abnormalities in AS might be reversible at some period after the time of birth. If successful, this project would provide a “proof of principle” that therapeutic initiatives might be successful after a child with AS is born. This work is ongoing but has initially met with success in generating the reversible mouse, although studies are pending.


Levodopa/carbidopa treatment of children with Angelman Syndrome

Dr. Lynne Bird, Rady Children’s Hospital, San Diego, CA

ASF has previously supported work at understanding if levodopa might have a potential therapeutic role in AS. This grant provides partial support to a larger clinical trial study which is aimed at implementing a controlled trial of levodopa supplementation to a group of children with AS. Individuals enrolled in the study will have a battery of developmental tests and neurological assessments periodically during a 1 to 2 year treatment phase.


Explore epigenetic therapy of using histone deacetylase inhibitors in the Angelman Syndrome mouse model

Dr. Yong-hui Jiang – Duke University Medical Center, Durham, NC

ASF has supported on many fronts research strategies in an attempt to increase the expression of UBE3A in the AS brain. As discussed for previous grants, it is known that in each nerve cell a UBE3A gene is repressed or silenced and is located on the paternally derived chromosome 15. One way to increase expression of UBE3A is to modify the imprinting control center (located near UBE3A) by trying to induce changes in the protein structure that surrounds or is adjacent to UBE3A. At present, the findings demonstrate that this avenue of gene treatment, while showing some promise, remains problematic since significant expression of the otherwise silenced gene is difficult to obtain.


Towards gene therapy for Angelman Syndrome using artificial transcription factors

Dr. David Segel – University of California Davis, Davis, CA

Dr. Segal has significant experience in synthesizing molecules that bind to DNA and are able to regulate gene activity. ASF has provided funds to this investigator to pursue the possibilities that such agents, called artificial transcription factors, could have an effect of increasing the expression of paternal UBE3A. These transcription factors could operate either very close to UBE3A or in regions some distance away, for example where the imprinting control center is located. To date, although preliminary work was encouraging, no viable transcription factor has been identified that brings about significant activation of the otherwise silenced UBE3A.


Neuregulin-dependent alterations in glutamate receptor function and LTP in Angelman Syndrome model mice

Dr. Eric Klann – New York University, New York, NY

How can we better understand the problems of intellectual deficiency in AS?  Recently it has been clear that one key to answering this question resides in better understanding of how neuronal synapses function. Neuregulins are important proteins involved in synapse function as they help reorganize and fully develop the synapse so that it is better able to respond to the types of stimulations and experiences that result in learning and memory. Dr. Klann’s studies have delineated how neuregulins  relate to synaptic development and how neuregulins are affected in the Angelman mouse model, and they provide one more important link to our better understanding of the synapse problems in AS.


Restoration of neocortial plasticity in a mouse model of Angelman Syndrome

Dr. Michael Ehlers – Duke University Medical Center, Durham, NC

In this research project, AS mice were studied at the time of birth and throughout the early days of life under controlled conditions that create different degrees of visual experience. This project was funded in collaboration with Dr. Philpot (see below) and extended further our understanding or how AS neurons behave and change under different stress conditions. In this situation, AS mice were housed in light and dark environments. Their neurons in the visual cortex were studied to document electrophysiological changes in single neurons. This work proved that AS neurons can undergo favorable developmental changes under certain conditions.


Restoration of neocortial plasticity in a mouse model of Angelman Syndrome

Dr. Benjamin Philpot – University of North Carolina at Chapel Hill, Chapel Hill, NC

An important question about the developmental problems in AS is to what extent neurons change based on experience and how this is impaired in AS. One way to understand this is to use the Angelman mouse model to study neurons in the occipital visual cortex and determine how they adjust and adapt to new visual stimuli (see above for Michael Ehlers). The work involved measuring cell activity using exquisite methods of micro manipulation and electrical recordings of individual neurons. This work was important in establishing that under certain experimental conditions the neurons from mice with AS were capable of achieving relatively normal electrophysiological activity.


A combined molecular and electrophysiological approach to understanding cerebellar defects in Angelman syndrome

Dr. Larry Reiter – The University of Tennessee, Memphis, TN

Individuals with AS have movement problems and are unstable walking. These findings have suggested that the cerebellum plays an important role in AS in causing these problems. In the Angelman mouse model, cerebellar function can be studied through the use of certain coordinated repetitive behaviors such as feeding and licking behaviors and that has been the basis for these studies. The purpose of this grant is to study these behaviors in the Angelman mouse model combined with detailed histological and protein chemistry studies of cerebellar neurons, and other neurons and cells in other brain regions.


The significance of EEG findings in Angelman Syndrome

Dr. Ronald Thibert – Massachusetts General Hospital, Boston, MA

It is known that individuals with AS have an abnormal EEG during periods when seizures do not occur as well as when seizures do occur. Although the patterns of EEG abnormalities have been previously described in AS, there has been little work that correlates EEG patterns to the severity of epilepsy, or that compares individuals with AS who have different genetic mechanisms. This project analyzes many EEGs from individuals throughout the United States. This work builds upon previous experience this investigator has had in AS through involvement in a survey-based analysis of seizures among the Angelman community.