Spine defects and synaptic dysfunction are common to neurodevelopmental disorders characterized by cognitive impairments in language, learning and sensory processing. Angelman Syndrome (AS) is a disorder caused by mutation of the maternal Ube3a allele, resulting in neuronal loss of the encoded ubiquitin ligase via developmental paternal imprinting. Delayed milestones are evident at 6-12 months of age, with progression to seizures and autistic features that include impaired speech, intellectual disability, altered social behaviors, and aberrant responses to sensory stimuli, including aversions to certain odors, flavors and textures. AS pathogenesis is not well understood; Ube3a participates in multiple cellular processes, including turnover of synaptic proteins. Spine defects, impaired synaptic plasticity, and deficits in cortical inhibitory drive are found in adult and juvenile AS mouse models, however it is not known how Ube3a loss impacts early stages of neuronal maturation and circuit integration. Gene reinstatement has established an early requirement for Ube3a in which the critical window for full phenotypic rescue occurs during prenatal/neonatal development, and we hypothesize that pathogenesis begins at this time, while newly-imprinted neurons are still maturing and engaged in circuit assembly. Intriguingly, selective loss of Ube3a in GABAergic interneurons reproduces features of circuit dysfunction caused by pan-neuronal loss, highlighting GABAergic neurons potential therapeutic targets. Adult-born interneurons that integrate in the adult olfactory bulb (OB) are subject to the same mutation effects as those born in embryo. In our work, we found that while Ube3a is absent in most brain regions in AS mice, the adult olfactory system shows a pattern of Ube3a expression that allows us to monitor paternal imprinting as new GABAergic granule cells (GCs) are generated, migrate, and mature in the OB. Moreover, we find that new, 35 day-old GCs show spine abnormalities. In this exploratory work, we propose to test the hypothesis that imprinting-mediated loss of Ube3a disrupts subsequent GC maturation, and that as a consequence, spine development is impaired.
Study aims will test this by defining a precise temporal profile of paternal imprinting in birth- dated GCs, and cell reconstruction/quantitative morphological analyses will identify emerging structural abnormalities relative to the timing of Ube3 loss. How the mutation affects olfaction is unknown, and in the final aim we will use a modified social interaction test to evaluate innate responses to conspecific odors. The overall goal of this project is to identify developmental defects that emerge from Ube3a loss in GCs to gain an understanding of both its normal role in GC maturation, and interneuron pathobiology in AS.

Public Health Relevance

Angelman Syndrome (AS) is a neurodevelopmental disorder, caused by mutation of the Ube3a gene, that has a high comorbidity with autism. Sensory dysfunction is common to AS and autism, and adverse reactions to tactile and chemosensory stimuli are reported by parents of AS children, leading to selective food avoidance that complicates nutritional management. Inhibitory neurons and circuits show abnormalities in the mature AS brain, and the goal of this work is to determine how maturation-related loss of Ube3a alters the structural growth and integration of new inhibitory interneurons in the olfactory system, in order to provide insight into early developmental effects of mutation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DC016467-01A1
Application #
9604937
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Sullivan, Susan L
Project Start
2018-06-12
Project End
2020-05-31
Budget Start
2018-06-12
Budget End
2019-05-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Florida Atlantic University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
004147534
City
Boca Raton
State
FL
Country
United States
Zip Code
33431