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.
Highlights
Autism-spectrum disorders (ASD) are heterogeneous neurodevelopmental disorders of yet poorly understood etiology that are characterized by severe socio-communicative deficits, restricted interests, stereotypies, and repetitive behaviors (Kanner, 1943; Asperger, 1944; American Psychiatric Association, 2013)
Mutations of genes encoding for synaptic proteins including neuroligins, neurexins, CNTNAP2, and SHANK3 have been associated with monogenic heritable ASD (Kumar and Christian, 2009; Huguet et al, 2013)
We show here that (1) Ambra1+/− mice display autism-like symptoms, including social interaction and communication deficits, repetitive behaviors, and cognitive rigidity
Summary
Autism-spectrum disorders (ASD) are heterogeneous neurodevelopmental disorders of yet poorly understood etiology that are characterized by severe socio-communicative deficits, restricted interests, stereotypies, and repetitive behaviors (Kanner, 1943; Asperger, 1944; American Psychiatric Association, 2013). Evidence has accumulated indicating that synaptic dysfunction, including changes in neurotransmission, plays a crucial role in the pathophysiology of ASD. Mutations of genes encoding for synaptic proteins including neuroligins, neurexins, CNTNAP2, and SHANK3 have been associated with monogenic heritable ASD (Kumar and Christian, 2009; Huguet et al, 2013). Knockout of the eukaryotic translation initiation factor 4E-binding protein 2, an eIF4E repressor, or eIF4E overexpression leads to an increase in neuroligins and ASD-like phenotypes (Gkogkas et al, 2013). The etiology of ASD directly or indirectly converges at the synapse, introducing the term “synaptopathy” for ASD (Zoghbi and Bear, 2012; Delorme et al, 2013)
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