Maternal Loss of Ube3a Impairs Experience-Driven Dendritic Spine Maintenance in the Developing Visual Cortex.
Dendritic spines are a morphological feature of the majority of excitatory synapses in the mammalian neocortex and are motile structures with shapes and lifetimes that change throughout development. Proper cortical development and function, including cortical contributions to learning and memory formation, require appropriate experience-dependent dendritic spine remodeling. Dendritic spine abnormalities have been reported for many neurodevelopmental disorders, including Angelman syndrome (AS), which is caused by the loss of the maternally inherited UBE3A allele (encoding ubiquitin protein ligase E3A). Prior studies revealed that UBE3A protein loss leads to reductions in dendritic spine density and diminished excitatory synaptic transmission. However, the decrease in spine density could come from either a reduction in spine formation or an increase in spine elimination. Here, we used acute and longitudinal in vivo two-photon microscopy to investigate developmental and experience-dependent changes in the numbers, dynamics, and morphology of layer 5 pyramidal neuron apical dendritic spines in the primary visual cortex of control and AS model mice (Ube3a(m-/p+) mice). We found that neurons in AS model mice undergo a greater elimination of dendritic spines than wild-type mice during the end of the first postnatal month. However, when raised in darkness, spine density and dynamics were indistinguishable between control and AS model mice, which indicates that decreased spine density in AS model mice reflects impaired experience-driven spine maintenance. Our data thus demonstrate an experience-dependent anatomical substrate by which the loss of UBE3A reduces dendritic spine density and disrupts cortical circuitry.



Reduced dendritic spine densities are common in the neurodevelopmental disorder Angelman syndrome (AS). Because prior reports were based on postmortem tissue, it was unknown whether this anatomical deficit arises from decreased spine formation and/or increased spine elimination. Here, we used in vivo two-photon imaging to track spines over multiple days in a mouse model of AS. We found that spine formation is normal, but experience-dependent spine maintenance is reduced in the visual cortex of AS model mice. Our data pinpoint the anatomical process underlying the loss of dendritic spines, which can account for the decreased excitatory synaptic connectivity associated with AS. Therefore, normalizing spine maintenance is a potential therapeutic strategy.
Department of Cell Biology and Physiology, Neuroscience Center, and.
Hyojin
H
Kim
Department of Cell Biology and Physiology, Neuroscience Center, and Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, North Carolina 27599, and.
Portia A
PA
Kunz
Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina 27710.
Richard
R
Mooney
Department of Cell Biology and Physiology, Neuroscience Center, and Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, North Carolina 27599, and bphilpot@med.unc.edu slab@unc.edu.
Benjamin D
0000-0003-2746-9143
BD
Philpot
Department of Cell Biology and Physiology, Neuroscience Center, and Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, North Carolina 27599, and bphilpot@med.unc.edu slab@unc.edu.
Spencer L
0000-0002-2021-7034
SL
Smith
D017204:Angelman Syndrome / Q000235:genetics*; D000818:Animals; D003712:Dendrites / Q000378:metabolism*; D049229:Dendritic Spines / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019579:Neocortex / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D017966:Pyramidal Cells / Q000378:metabolism; D013569:Synapses / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D014793:Visual Cortex / Q000378:metabolism*
D049452:Green Fluorescent Proteins; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases
Angelman syndrome; E6AP; Ube3a; dendritic spine; two-photon; visual cortex