Abstract
Heterozygous mutation of Ambra1, known as a positive autophagy regulator, produces autismlike behavior in mice and autistic phenotypes in humans in a female-specific manner. However, the substantial roles of the Ambra1 mutation in neurons are still unknown. We find that Ambra1 heterozygotes display a moderate decrease in excitatory synaptic release in-vitro and ex-vivo exclusively in females without autophagy activity, resulting in significant alterations in γ-oscillation power and seizure susceptibility by excitatory/inhibitory (E/I) imbalance. Specifically, Ambra1 deficiency has no effect on neurogenesis and morphogenesis, but selectively decreases excitatory synaptic activity without changes in synapse number, quantal size, synaptic release probability, and synaptic plasticity. Therefore, the limited excitatory synaptopathy by Ambra1 expression levels ultimately determines E/I imbalance in global neural networks leading to the female-specific ASD.
Competing Interest Statement
Nils Brose (NB) is under competing interests for being a reviewing editor of this journal. Other authors declare that there is no competing of interest.
Footnotes
This new version of the article contains a corrected version of panel A in Supplementary Figure S1. In the original version, the left and middle columns of this panel were inadvertently assembled using images of Memcode-stained blots from an iteration of the experiment that did not correspond to the respective Western blot images. In the corrected version of the figure, Memcode and Western blot images in each column are from the same experiments