Thursday, May 17, 2012
Sheraton Hall (Sheraton Centre Toronto)
11:00 AM
P. A. McCoy1,2 and B. D. Philpot1,2,3, (1)Cell and Molecular Physiology, UNC, Chapel Hill, NC, (2)Carolina Institute for Developmental Disabilities, UNC, Chapel Hill, NC, (3)Neuroscience Center, UNC, Chapel Hill, NC
Background: Ubiquitin-protein ligase E3A (UBE3A, also called E6-AP) is a HECT domain ubiquitin ligase that is encoded for by the
UBE3A gene. In many regions of the CNS,
UBE3A undergoes neuronal-specific paternal imprinting, meaning that
UBE3A is expressed from only the maternal allele. Changes in the gene dosage of
UBE3A are strongly linked to neurodevelopmental disorders such that increased gene dosage of maternal
UBE3A has been strongly implicated in autism, while loss-of-function of maternal
UBE3A causes the severe mental retardation disorder Angelman syndrome (AS), also an autism spectrum disorder. Both disorders are characterized by functionally severe intellectual and developmental delays, lack of speech, epilepsy, movement disorders, and other behavioral deficits. Interestingly, abnormal dendritic spine numbers and morphology have been observed in
Ube3a-deficient mice, as well as in human patients postmortem tissue, suggesting that cognitive impairments associated with AS may arise from deficits in structural synaptic plasticity. Consistent with this idea, UBE3A has been shown to be necessary for experience-dependent wiring of the neocortex during the sensory critical period where there is robust structural and electrophysiological synaptic plasticity.
Objectives: To determine Ube3a’s role in the structural plasticity of synapses during the experience-driven formation of neuronal circuits.
Methods: We performed in vivo 2-photon time-lapse imaging of visual cortical neurons, expressing a Thy-1 driven GFP reporter, in maternally Ube3a-deficient (Ube3am-/p+) AS model mice and wildtype (WT) littermates during the critical period of development (P21-30).
Results: General spine density analysis confirmed previous reports that loss of UBE3A results in a decrease in spine number. To determine if this is due to a decrease in spine formation or an increase in spine elimination, blind analysis of these rates as well as the rate of spine turnover is ongoing.
Conclusions: Cognitive impairments associated with AS could arise due to an altered rate of spine turnover as a consequence of deficits in spine dynamics during the critical period for neocortical maturation. This model can be used to determine how changes in structural plasticity are affected by loss of UBE3A during development and may be used to determine the efficacy of potential AS treatments for functional recovery.
