Chemogenetic elevation of hippocampal excitability unmasks latent ASD risks in non-autistic mice differing in hippocampal AMBRA1 expression and/or sex

Among the genomic alterations identified as risk factors in Autism Spectrum Disorders (ASD), haploinsufficiency of AMBRA1 (Activating Molecule in Beclin1-Regulated Autophagy) triggers an ASD phenotype associated with hippocampal hyperexcitability exclusively in the female sex. Remarkably, AMBRA1 protein is constitutively more expressed in the hippocampus of wild-type (Wt) females than males. However, being more decreased by AMBRA1 deficiency in the female than the male sex, it results comparably expressed in the hippocampus of autistic females and non-autistic males. In this study, we verified whether milder AMBRA1 downregulation in mutant males, and lower constitutive AMBRA1 expression in Wt males, although insufficient to trigger autistic traits, might underlie latent risks to become autistic in situations that increase excitability in ASD circuits. Here we report that activation of inhibitory DREADDs in CA1 parvalbuminergic interneurons (PV-IN) increases CA1 pyramidal neurons (PN) excitability, causes social and attentional deficits, and augments immature/thin spines in PN dendrites in mutant males and Wt mice of both sexes. On the one hand, our results reveal that chemogenetic increase of CA1 excitability in male mice triggers ASD traits regardless of mutation indicating the existence of a threshold below which downregulation of AMBRA1 from constitutive levels is uninfluential to ASD. On the other, DREADDs induction of comparable ASD traits in Wt mice regardless of sex indicates that, despite their robust differences in AMBRA1 expression, Wt males and females are both prone to become autistic in situations that selectively increase hippocampal excitability.