Daniel Montgomery PhD Submitted:

Angelman syndrome (AS) is associated with elevated delta (1-4 Hz) EEG power, a robust, translatable biomarker linked to clinical severity. AS causes increased cortical delta oscillations in both children with AS and in Ube3a^m-/p+ mice; however, little is known about how loss of UBE3A/Ube3a drives delta oscillations at a mechanistic level.

In typical development, delta oscillations occur primarily during NREM sleep and are generated by interactions between thalamic and cortical circuits: thalamic reticular nucleus (TRN) neurons inhibit thalamic relay neurons, driving them into a burst firing mode that rhythmically excites cortex. Yet whether the excess delta in AS arises from dysfunction in thalamic or cortical components of this circuit remains unknown.

We recorded local field potentials and single unit activity simultaneously in primary visual cortex (V1) and either the lateral geniculate nucleus (LGN) or TRN of wild-type and Ube3a^m-/p+ mice.

Elevated delta power in Ube3a^m-/p+ mice was driven by increased time spent in delta episodes rather than greater power within episodes. LGN burst firing was elevated in Ube3a^m-/p+ mice, but only in proportion to the increased time spent in delta oscillations, with normal burst rates within delta episodes.

TRN bursting was unexpectedly impaired in Ube3a^m-/p+ mice, arguing against the TRN as the driver of elevated delta. In cortex, fast-spiking (putative PV+) interneuron firing rates were reduced, and LGN bursts evoked significantly stronger cortical responses, consistent with weakened feedforward inhibition lowering the threshold for thalamocortical delta recruitment.

Together, these results suggest that cortical inhibitory dysfunction, rather than thalamic circuitry, represents the primary driver of the AS delta phenotype. These findings establish a mechanistic framework linking UBE3A loss to a defining EEG signature of AS, laying the groundwork for future circuit-informed therapeutic strategies.