Collections > Electronic Theses and Dissertations > Cortical experience-dependent plasticity and mesostriatal dopaminergic dysfunction in a mouse model of Angelman syndrome

Sensory experience guides development of neocortical circuits. This activity-dependent circuit maturation is required for normal sensory and cognitive abilities, which are distorted in neurodevelopmental disorders. Here we have tested whether experience-dependent cortical modifications require Ube3a, an E3 ubiquitin ligase whose dysregulation has been implicated in both autism and Angelman syndrome (AS). Using the visual cortex as a model system for neocortical plasticity, we found that the genetic deletion of UBE3A attenuates activity-dependent synaptic strengthening and weakening in visual cortical slices. Chronic recordings of visual evoked potentials (VEPs) from awake mice also exhibited deficits in critical period ocular dominance plasticity, an in vivo assay for experience-dependent synaptic weakening. Stimulus-specific response potentiation (SRP) of VEPs was used as an assay of experience-dependent synaptic strengthening. Contrary to the results observed in in vitro slice preparations, we observed developmentally enhanced potentiation of VEPs, including increased power of spontaneous local field potentials (LFP) in AS mice. WT and AS mice achieved similar increases in VEP amplitude with a longer period of visual stimulation, indicating the threshold for potentiation was lower in AS mice. Augmented plasticity and increased spontaneous LFP power were absent from mice maternally expressing Ube3a in inhibitory neurons alone. Our results suggest that sensory experience-dependent cortical potentiation is enhanced in adult AS mice due to reduced inhibition. Previous studies also suggest that abnormal dopamine neurotransmission may underlie some of the motor deficits exhibited in AS. A clinical trial of levodopa (L-DOPA) in AS is ongoing, although the underlying rationale for this treatment strategy has not yet been thoroughly examined in preclinical models. We found that AS mice exhibited behavioral deficits that correlated with abnormal dopamine signaling. These deficits were not due to loss of dopaminergic neurons or impaired dopamine synthesis. Unexpectedly, AS mice exhibited increased dopamine release in the mesolimbic pathway while also exhibiting a decrease in dopamine release in the nigrostriatal pathway, as measured with fast-scan cyclic voltammetry. These findings demonstrate the complex effects of UBE3A loss on dopamine signaling in subcortical motor pathways that may inform ongoing clinical trials of L-DOPA therapy in patients with AS.