Abstract
The neurodevelopmental disorder Angelman syndrome (AS) is characterized by intellectual disability, motor dysfunction, distinct behavioral aspects, and epilepsy. AS is caused by a loss of the maternally expressed UBE3A gene, and many of the symptoms are recapitulated in a Ube3a mouse model of this syndrome. At the cellular level, changes in the axon initial segment (AIS) have been reported, and changes in vesicle cycling have indicated the presence of presynaptic deficits. Here we studied the role of UBE3A in the auditory system by recording synaptic transmission at the calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB) through in vivo whole cell and juxtacellular recordings. We show that MNTB principal neurons in Ube3a mice exhibit a hyperpolarized resting membrane potential, an increased action potential (AP) amplitude and a decreased AP half width. Moreover, both the pre- and postsynaptic AP in the calyx of Held synapse of Ube3a mice showed significantly faster recovery from spike depression. An increase in AIS length was observed in the principal MNTB neurons of Ube3a mice, providing a possible substrate for these gain-of-function changes. Apart from the effect on APs, we also observed that EPSPs showed decreased short-term synaptic depression (STD) during long sound stimulations in AS mice, and faster recovery from STD following these tones, which is suggestive of a presynaptic gain-of-function. Our findings thus provide in vivo evidence that UBE3A plays a critical role in controlling synaptic transmission and excitability at excitatory synapses.
Highlights
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of the maternal allele of the ubiquitin ligase E3A (UBE3A) gene
Immunohistochemistry showed a strong reduction of UBE3A protein throughout the brain (Figure 1B)
Our observations indicate that the Ube3a mouse is a gain of function mutant for synaptic transmission in the calyx of Held synapse
Summary
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of the maternal allele of the UBE3A gene. AS has an incidence of 1:25,000 and affects both genders (Mertz et al, 2013). The disorder is associated with intellectual disability, profound speech impairment, motor abnormalities, epilepsy, and specific behavioral abnormalities including autism and impaired sleep rhythm (reviewed in Buiting et al, 2016). UBE3A encodes the ubiquitin ligase E3A (UBE3A; termed E6-associated protein, E6-AP), which is expressed solely from the maternal allele in mature neurons. Ubiquitin ligase E3A covalently attaches polyubiquitin chains to proteins, resulting in either their degradation by the 26S proteasome or an impact on their. In Vivo Synaptic Transmission in Ube3a Mice activity. Several substrates have been identified, it is not clear to what extent these targets contribute to the AS phenotype
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
