Collections > Electronic Theses and Dissertations > Circuit and neuron type-specific roles for Ube3a in the visual cortex

Balanced excitation and inhibition is critical for normal circuit function and disruptions in excitation-to-inhibition (E/I) balance have been shown to exist in many neurological disorders. One such disorder, autism, has been hypothesized to result from genetic and/or environmental insults that cause an E/I imbalance in key neural circuits/systems. Angelman syndrome (AS) is an autism spectrum disorder distinguished by severe intellectual disabilities, EEG abnormalities, gait disturbances, disrupted sleep patterns, profound language impairment, and seizures. AS is caused by deletions or loss-of-function mutations in the maternally inherited allele of UBE3A. Similar to humans with AS, AS model mice lacking the maternal Ube3a allele exhibit behavioral changes mirroring the hallmarks of the syndrome, including abnormal EEG patterns, elevated seizure susceptibility, and difficulty with movement and balance. Seizures are believed to be extreme manifestations of E/I imbalance, therefore we hypothesized that there existed an E/I imbalance in cortical circuits in AS model mice. We investigated excitatory and inhibitory neurotransmission in the visual cortex and found an inhibitory deficit that may arise from defective presynaptic vesicle cycling in multiple interneuron populations. The inhibitory defect is specific to inputs into excitatory neurons as neurotransmission onto inhibitory neurons is normal. Excitatory neurotransmission onto excitatory neurons are also decreased but to a smaller degree leading to an E/I imbalance in cortical circuits. We then sought to determine the neuron type-specific requirements for Ube3a in regulating E/I imbalance. We used mice harboring a conditional Ube3a allele to show that deleting Ube3a from all inhibitory neurons resulted in none of the synaptic phenotypes observed when Ube3a was deleted from all neurons. Furthermore, when we deleted Ube3a from cortical excitatory neurons we observed only defects in evoked inhibition. These findings suggest Ube3a loss is required both pre and postsynaptically for several synaptic phenotypes contributing to E/I imbalance observed in AS model mice. Together, these studies identify a synaptic mechanism underlying E/I imbalance in cortical circuits and may lead to more effective treatments for seizures in AS.