Voor het Angelman Syndroom

Experiences fail to guide brain maturation in Angelman syndrome model mice

In the study "Ube3a is required for experience-dependent maturation of the neocortex" by Yashiro and colleagues, the authors examined how the neocortex (1) develops in Angelman syndrome model mice. These mice lack normal expression of the Ube3a (2) protein in the brain, which is the critical hallmark in all genetic forms of Angelman syndrome. The authors focused their studies on the visual cortex, as this region of the brain has a well-defined critical period during which visual experiences remodel the connections between neurons (3).

The authors examined how the neuronal circuitry of normal and Angelman syndrome mice changed across development, and found that neuronal interconnectivity was diminished in Angelman syndrome model mice. While visual experiences increase the number of connections between neurons in normal mice, no such increase was observed in Angelman syndrome mice. The lack of experience-dependent remodeling in brain circuitry may be a consequence of an impaired ability of synapses (4) to strengthen and weaken.

While the ability of synapses to strengthen and weaken was impaired in Angelman syndrome mice, the researchers showed that normal brain plasticity can be restored by sensory deprivation. This indicates that brain cells in Angelman syndrome patients maintain the molecular machinery to express normal brain plasticity.

Implications: Normally brain cells wire together by following a genetic program of development that is modified through sensory experiences. This experience-dependent component of brain maturation provides a sensory feedback mechanism to ensure that the proper connections are maintained while inappropriate connections are eliminated. Although much of the developmental program for wiring the brain is intact in Angelman syndrome mice, these mice lack the experience-dependent component of brain maturation. This developmental defect is associated with profound impairments in the normal ability of synapses to strengthen and weaken in response to changes in neural activity. These results show that Ube3a is required for the proper experience-dependent maturation of the neocortex, and suggest that the loss of neocortical plasticity contributes to the cognitive deficits associated with Angelman syndrome.

The observations that plasticity could be restored by sensory deprivation suggest that the neurons in Angelman syndrome mice maintain a dormant ability to express synaptic plasticity (5). While sensory deprivation is obviously not a viable treatment therapy, the demonstration that brain plasticity can be restored raises the remarkable possibility that this latent ability to express plasticity can be tapped through behavioral, pharmacological, or genetic manipulations to treat Angelman syndrome.

(1) Neocortex: The outer layers of the brain. It is used as a repository for memories and is necessary for higher cognitive functions. This region, whose representation is increased in non-human primates and humans, presumably endows primates with higher cognitive abilities. (2) UBE3A: UBE3A is a human gene that provides instructions for making the enzyme ubiquitin protein ligase E3A. The UBE3A gene is located on the long (q) arm of chromosome 15 between positions 11 and 13.

(3) Neuron: A class of cells that is primarily responsible for information flow in the brain.

(4) Synapse: The microscopic point of communication between neurons.

(5) Synaptic plasticity: The ability to strengthen or weaken the connections (synapse)s between neurons in the brain, and/or the ability to anatomically remodel connections between neurons.

Preclinical studies of neocortical development and plasticity in Angelman syndrome

Article information:
Title: Ube3a is required for experience-dependent maturation of the neocortex.
Authors: Yashiro K, Riday TT, Condon KH, Roberts AC, Bernardo DR, Prakash R, Weinberg RJ, Ehlers MD, Philpot BD
Journal: Nature Neuroscience, 2009, published online May 10.

(Contributed by Koji Yashiro and Ben Philpot)