Correlative and conventional EM: an integrated strategy to bridge synapse ultrastructure and neuronal dysfunction in Angelman Syndrome

Angelman Syndrome (AS) is a neurodevelopmental disorder of genetic origin arising from the loss of the maternal copy of the ubiquitin protein ligase E3A (UBE3A) gene. UBE3A encodes for E3A protein which is involved in transcription activation and protein degradation. While UBE3A is biallelically expressed throughout the body, in neurons only the maternal allele is active because the paternal one is silenced by genomic imprinting. As a result, neurons are extremely sensible to UBE3A loss, which can originate from various genetic mechanisms: de novo deletions on the maternal 15q11-q13 region, paternal uniparental disomy, imprinting defects or point mutations. Genomic alterations leading to an unproper UBE3A dosage are directly responsible for defects in brain development and synapse ultrastructure. In this scenario, the nano-resolution power of Electron Microscopy (EM) has proven essential for studying their outcome at the network level and establishing meaningful correlations between synapses geometrical features and function. Here, I apply a dual approach – combining conventional Transmission Electron Microscopy (TEM) with volume Correlative Light and Electron Microscopy (vCLEM) – to delve into the mechanisms of neuronal dysfunction in AS.