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Role of Ube3a in neocortical plasticity and function

Ben Philpot, Ph.D.
University of North Carolina at Chapel Hill

Michael D. Ehlers, M.D., Ph.D.
Duke University

Angelman syndrome is a severe neurodevelopmental disorder characterized by intellectual disability, motor dysfunction, seizures and the absence of speech, and it shows a high comorbidity with autism. The syndrome is caused by maternal deletion or mutation of a single gene that encodes the ubiquitin protein ligase E3A (UBE3A). The paternal copy of UBE3A is silenced in neurons, and therefore the loss of maternal UBE3A results in a complete absence of the protein in most areas of the brain. UBE3A is an enzyme that targets proteins for degradation, a process that maintains normal functioning within cells.

In 2009, the labs of Benjamin Philpot, of the University of North Carolina at Chapel Hill, and Michael Ehlers, then at Duke University and now chief scientific officer of neuroscience at Pfizer, discovered that UBE3A is required for experience-dependent maturation of the neocortex, which comprises the outer layers of the brain and is involved in higher cognitive functions1. The researchers found that normal synaptic plasticity, the ability to strengthen and weaken connections between neurons, is preserved under conditions of sensory deprivation but is rapidly lost by sensory experiences.

The loss of neocortical plasticity in Angelman syndrome mice is reversible, as late-onset visual deprivation restores normal synaptic plasticity. These findings demonstrate that normal UBE3A expression is necessary to maintain experience-dependent remodeling in the brain, and that the loss of neocortical plasticity might contribute to the deficits associated with Angelman syndrome and possibly other forms of autism caused by dysregulation of UBE3A.

Building upon these findings, the Philpot lab demonstrated that the loss of UBE3A causes a profound excitatory/inhibitory imbalance in the neocortex through cell-type-specific defects2. This imbalance arose from a disproportionate loss of inhibitory synapse function onto excitatory pyramidal neurons (cells in the brain that transmit information) and also, at least in part, from defective presynaptic vesicle cycling (a cellular process that helps maintain synapse functions). In contrast to the severe synaptic defects onto pyramidal neurons, excitatory and inhibitory synaptic inputs onto inhibitory interneurons are largely unaffected by the loss of UBE3A.

These results indicate that there are neuron-type-specific synaptic deficits in Angelman syndrome model mice despite the presence of UBE3A in all neurons. The excitatory/inhibitory imbalance at the cellular and circuit levels caused by the loss of UBE3A may contribute to seizure susceptibility in Angelman syndrome.

References:

1: Yashiro K. et al. Nat. Neurosci. 12, 777-783 (2009) PubMed

2: Wallace M.L. et al. Neuron 74, 793-800 (2012) PubMed


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