E3 ubiquitin ligase (UBE3A) levels in the brain need to be tightly regulated, as loss of functional UBE3A protein is responsible for the severe neurodevelopmental disorder Angelman syndrome (AS), whereas increased activity of UBE3A is associated with nonsyndromic autism. Given the role of mPFC in neurodevelopmental disorders including autism, we aimed to identify the functional changes resulting from loss of UBE3A in infralimbic and prelimbic mPFC areas in a mouse model of AS. Whole-cell recordings from layer 5 mPFC pyramidal neurons obtained in brain slices from adult mice of both sexes revealed that loss of UBE3A results in a strong decrease of spontaneous inhibitory transmission and increase of spontaneous excitatory transmission potentially leading to a marked excitation/inhibition imbalance. Additionally, we found that loss of UBE3A led to decreased excitability and increased threshold for action potential of layer 5 fast spiking interneurons without significantly affecting the excitability of pyramidal neurons. Because we previously showed that AS mouse behavioral phenotypes are reversible upon Ube3a gene reactivation during a restricted period of early postnatal development, we investigated whether Ube3a gene reactivation in a fully mature brain could reverse any of the identified physiological deficits. In contrast to our previously reported behavioral findings, restoring UBE3A levels in adult animals fully rescued all the identified physiological deficits of mPFC neurons. Moreover, the kinetics of reversing these synaptic deficits closely followed the reinstatement of UBE3A protein level. Together, these findings show a striking dissociation between the rescue of behavioral and physiological deficits.

Autistic disorder, Disease models, Ion channel, Prefrontal cortex, Synaptic transmission, UBE3A
dx.doi.org/10.1523/JNEUROSCI.0083-18.2018, hdl.handle.net/1765/110351
The Journal of Neuroscience
ENCORE Center for Neurodevelopmental Disorders

Rotaru, D.C, van Woerden, G.M, Wallaard, I, & Elgersma, Y. (2018). Adult Ube3a gene reinstatement restores the electrophysiological deficits of prefrontal cortex layer 5 neurons in a mouse model of angelman syndrome. The Journal of Neuroscience, 38(37), 8011–8030. doi:10.1523/JNEUROSCI.0083-18.2018