Sexual dimorphism of AMBRA1-related autistic features in human and mouse

Abstract

Ambra1 is linked to autophagy and neurodevelopment. Heterozygous Ambra1 deficiency induces autism-like behavior in a sexually dimorphic manner. Extraordinarily, autistic features are seen in female mice only, combined with stronger Ambra1 protein reduction in brain compared to males. However, significance of AMBRA1 for autistic phenotypes in humans and, apart from behavior, for other autism-typical features, namely early brain enlargement or increased seizure propensity, has remained unexplored. Here we show in two independent human samples that a single normal AMBRA1 genotype, the intronic SNP rs3802890-AA, is associated with autistic features in women, who also display lower AMBRA1 mRNA expression in peripheral blood mononuclear cells relative to female GG carriers. Located within a non-coding RNA, likely relevant for mRNA and protein interaction, rs3802890 (A versus G allele) may affect its stability through modification of folding, as predicted by in silico analysis. Searching for further autism-relevant characteristics in Ambra1+/− mice, we observe reduced interest of female but not male mutants regarding pheromone signals of the respective other gender in the social intellicage set-up. Moreover, altered pentylentetrazol-induced seizure propensity, an in vivo readout of neuronal excitation–inhibition dysbalance, becomes obvious exclusively in female mutants. Magnetic resonance imaging reveals mild prepubertal brain enlargement in both genders, uncoupling enhanced brain dimensions from the primarily female expression of all other autistic phenotypes investigated here. These data support a role of AMBRA1/Ambra1 partial loss-of-function genotypes for female autistic traits. Moreover, they suggest Ambra1 heterozygous mice as a novel multifaceted and construct-valid genetic mouse model for female autism.

AMBRA1, Autophagy, and the Extreme Male Brain Theory of Autism

“…First, the AMBRA1 SNP rs3802890 genotype showed strong sex specificity in its phenotypic effects, with restriction to females. These results corroborate and extend previous analyses of mice and humans [8, 10, 17], all of which show female-restricted or female-biased effects on psychological, psychiatric, and neurological phenotypes.…”

“…Recently, Mitjans et al [10] showed that the AMBRA1 SNP rs3802890 was associated with measures of sociality in a cohort of individuals with schizophrenia, and in a cohort of typical individuals, with significant effects limited to females in both populations. Different SNPs of AMBRA1 have also been linked with risk of schizophrenia, although sex differences were not investigated here [13].…”

Ambra1 Shapes Hippocampal Inhibition/Excitation Balance: Role in Neurodevelopmental Disorders

“…Risk allele-carriers showed a higher blood oxygen level-dependent response in the prefrontal cortex during a flanker task, indicating that the risk allele is associated with impulsive-related traits [ 21 , 22 ] . Notably, a behavioral study on heterozygous Ambra1 mice (Ambra1 +/− ) revealed an autism-like phenotype that was restricted only to females [ 23 ] and a recent work proved an association between autism and intronic single nucleotide polymorphisms of the AMBRA1 gene in human female patients [ 24 ].…”

Age related retinal Ganglion cell susceptibility in context of autophagy deficiency

“…Recent studies, however, have revealed that female Ambra1 +/gt mice have some autistic features, but these are already apparent in young animals. Some of the analysed changes in the young animals however showed a slightly different characteristic in the middle aged mice, such as the form of induced seizures 53,54 , pointing towards a possible age related change. In our study we used a female to male ratio of 1:1 with an outbred CD1 background, whereas the studies showing autistic features were performed in Ambra1 +/gt with a C57BL/6N background and observations were only found in the female mice.…”