Abstract
ABSTRACTChanges in UBE3A expression levels in neurons can cause neurogenetic disorders ranging from Angelman syndrome (AS) (decreased levels) to autism (increased levels). Here we investigated the effects on neuronal function of varying UBE3A levels using the Drosophila neuromuscular junction as a model for both of these neurogenetic disorders. Stimulations that evoked excitatory junction potentials (EJPs) at 1 Hz intermittently failed to evoke EJPs at 15 Hz in a significantly higher proportion of Dube3a over-expressors using the pan neuronal GAL4 driver C155-GAL4 (C155-GAL4>UAS-Dube3a) relative to controls (C155>+ alone). However, in the Dube3a over-expressing larval neurons with no failures, there was no difference in EJP amplitude at the beginning of the train, or the rate of decrease in EJP amplitude over the course of the train compared to controls. In the absence of tetrodotoxin (TTX), spontaneous EJPs were observed in significantly more C155-GAL4>UAS-Dube3a larva compared to controls. In the presence of TTX, spontaneous and evoked EJPs were completely blocked and mEJP amplitude and frequency did not differ among genotypes. These data suggest that over-expression of wild type Dube3a, but not a ubiquitination defective Dube3a-C/A protein, compromises the ability of motor neuron axons to support closely spaced trains of action potentials, while at the same time increasing excitability. EJPs evoked at 15 Hz in the absence of Dube3a (Dube3a15b homozygous mutant larvae) decayed more rapidly over the course of 30 stimulations compared to w1118 controls, and Dube3a15b larval muscles had significantly more negative resting membrane potentials (RMP). However, these results could not be recapitulated using RNAi knockdown of Dube3a in muscle or neurons alone, suggesting more global developmental defects contribute to this phenotype. These data suggest that reduced UBE3A expression levels may cause global changes that affect RMP and neurotransmitter release from motorneurons at the neuromuscular junction. Similar affects of under- and over-expression of UBE3A on membrane potential and synaptic transmission may underlie the synaptic plasticity defects observed in both AS and autism.
Highlights
Angelman syndrome (AS) is a devastating human neurological disorder characterized by cognitive and behavioral defects, muscle hypotonia as well as jerky limb movements and a debilitating ataxic gait (Williams, 2005)
Dube3a Over-Expression A series of experiments were carried out to test the effects of over-expression of Dube3a on changes in evoked junction potential (EJP) amplitude at rapid stimulation rates
There was no significant difference between C155>Dube3a-51, C155>Dube3a-27, or C155>+ larva regarding the amplitude of the first EJP in the train or the average resting membrane potential (RMP) over the course of the train (ANOVA, p
Summary
Angelman syndrome (AS) is a devastating human neurological disorder characterized by cognitive and behavioral defects, muscle hypotonia as well as jerky limb movements and a debilitating ataxic gait (Williams, 2005). A mouse model with a duplication syntenic to human interstitial duplications of 15q11.2-q13, displayed behavioral deficits characteristic of autism, possibly caused by a deficit in 5-HT2c receptor signaling (Nakatani et al, 2009; Tamada et al, 2010). These data support the hypothesis that the level of UBE3A expressed from the maternal allele in neurons is critical to neuronal development and function; deficiency for maternal UBE3A resulting in Angelman syndrome and duplication of maternal UBE3A driving increased autism risk
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