UBE3A controls axon initial segment in the cortical pyramidal neurons

The axon initial segment (AIS) is a critical regulator of neuronal excitability and the initiation site of action potentials. Alterations in the structural features of AIS, such as length and position, have been shown to influence neuronal function, a phenomenon known as activity-dependent AIS plasticity. In addition to their physiological functions, abnormalities in the AIS have been implicated in various neurological disorders. UBE3A is an E3 ubiquitin ligase crucial for protein degradation in neurons. In mature neurons, only the maternal allele of the UBE3A gene is active, and the paternal allele is silenced. However, the role of UBE3A in controlling AIS in the cortical pyramidal neurons has not yet been fully elucidated. In this study, we compared wild-type mice with three different Ube3a-deficient mice and observed specific elongation of the AIS in the prelimbic cortex of the medial prefrontal cortex but not in the somatosensory cortex or motor cortex, as previously reported. Interestingly, we also showed that UBE3A controls AIS length in a cell-autonomous manner using cultured cortical neurons derived from Ube3a-floxed (Ube3a^flox/flox) mice. This study indicates that UBE3A controls AIS length through a cell-autonomous mechanism in vitro. However, non-cell-autonomous mechanisms, including feedback from inhibitory neurons or connections with the hippocampus, may also influence adult AIS length in vivo, thereby helping to maintain the excitability homeostasis of cortical pyramidal neurons in a region-specific manner.