Heterozygous Ambra1 Deficiency in Mice: A Genetic Trait with Autism-Like Behavior Restricted to the Female Gender

Abstract

Autism-spectrum disorders (ASD) are heterogeneous, highly heritable neurodevelopmental conditions affecting around 0.5% of the population across cultures, with a male/female ratio of approximately 4:1. Phenotypically, ASD are characterized by social interaction and communication deficits, restricted interests, repetitive behaviors, and reduced cognitive flexibility. Identified causes converge at the level of the synapse, ranging from mutation of synaptic genes to quantitative alterations in synaptic protein expression, e.g., through compromised transcriptional or translational control. We wondered whether reduced turnover and degradation of synapses, due to deregulated autophagy, would lead to similar phenotypical consequences. Ambra1, strongly expressed in cortex, hippocampus, and striatum, is a positive regulator of Beclin1, a principal player in autophagosome formation. While homozygosity of the Ambra1 null mutation causes embryonic lethality, heterozygous mice with reduced Ambra1 expression are viable, reproduce normally, and lack any immediately obvious phenotype. Surprisingly, comprehensive behavioral characterization of these mice revealed an autism-like phenotype in Ambra1+/− females only, including compromised communication and social interactions, a tendency of enhanced stereotypies/repetitive behaviors, and impaired cognitive flexibility. Reduced ultrasound communication was found in adults as well as pups, which achieved otherwise normal neurodevelopmental milestones. These features were all absent in male Ambra1+/− mice. As a first hint explaining this gender difference, we found a much stronger reduction of Ambra1 protein in the cortex of Ambra1+/− females compared to males. To conclude, Ambra1 deficiency can induce an autism-like phenotype. The restriction to the female gender of autism-generation by a defined genetic trait is unique thus far and warrants further investigation.

Phosphatidylserine Ameliorates Neurodegenerative Symptoms and Enhances Axonal Transport in a Mouse Model of Familial Dysautonomia

“…These behaviors are indicative of motor discoordination problems in CKO Tyrp2 FD mice [59]. Since FD patients exhibit inappropriate thermal and pain perception, we also performed hot plate analgesia assays as described previously [60]. At 3 months of age, CKO Tyrp2 FD mice exhibited less perception of sensation compared to age-matched controls (Fig 1K; mean ± SEM, 6.8±0.6 sec.…”

Ambra1 at a glance

“…) has revealed an autism-like phenotype in adult and pup females, including compromised social interactions, a tendency to exhibit stereotypies or repetitive behaviors and impaired cognitive flexibility (Dere et al, 2014). Another interesting pathological phenotype observed in these Ambra1 +/gt mice is a dramatically enhanced and prolonged neuropathic pain that occurs following a nerve insult and axonal degeneration (Marinelli et al, 2014).…”

“…In the context of pathology, AMBRA1 has, initially, been implicated in impaired embryogenesis and found to be involved in mouse congenital malformation and human neurological disorders (Dere et al, 2014;Fimia et al, 2007;Heinrich et al, 2013, Marinelli et al, 2014Rietschel et al, 2012;Skobo et al, 2014;Vázquez et al, 2012). Beyond this point, AMBRA1 is a bona fide tumor suppressor gene and has been found to be mutated in a significant percentage of human tumors of various tissues (Cianfanelli et al, 2015c).…”

Autophagy in synaptic development, function, and pathology

“…Although the molecular mechanism by which autophagy phenotypes in female mice [64] , implying that deregulation of the autophagic pathway causes the pathology of autism.…”