|dc.description.abstracteng||Autism is known as a heritable neurodevelopmental disorder, diagnosed prior to the age of three years in humans based on three major domains: (1) impairment in social interaction (2) communication deficits (3) restricted interests and repetitive behaviors. Since it is a very heterogeneous disorder with various causes and different combinations of phenotypes, it is also called autism spectrum disorder (ASD). Monogenic heritable forms of ASD enable us to develop genetic mouse models of autism in order to obtain mechanistic insight in this disorder.
Ambra1 is a positive regulator of Beclin1, a major player in the formation of autophagosomes during the process of autophagy. While Ambra1 null mutation leads to embryonic lethality, we could show that Ambra1 heterozygous mice (Ambra1+/-) display autism-like behavior only in females. Purpose of this thesis was therefore to characterize this mouse line further.
It turned out that communication deficits, measured by ultrasound vocalization, start in the neonatal stage of females, while physical or neurological development is normal in Ambra1+/-. Female Ambra1 mutants had a stronger reduction in Ambra1 expression than male mutants, which gives first hints of the female-specific autism-like behavior in this mouse line. Mild enlargement of whole brain and hippocampus was detected in both Ambra1+/- males and females, with no change of ventricle size. Since β-galactosidase, used as reporter expressed under the Ambra1 promoter, was found only in neuronal cells, I focused on understanding the neural mechanism of its phenotype.
Short-term and long-term synaptic plasticity in the hippocampus was normal for males and females of both genotypes. However, the power of gamma oscillations (γ-power), indicative of change in the balance of excitation and inhibition, was age-dependently altered in Ambra1+/- females only. However, this difference was not detected in male. Moreover, increased susceptibility to seizures, a known comorbid condition of ASD was restricted to females, suggesting an association between autism-like behavior, gamma oscillation and seizure propensity in female Ambra1+/- mice.
Next, I approached the neuronal substrate of these three phenotypes by morphological analysis of hippocampal pyramidal neurons, such as dendritic arborization and synapse number. A genotype-associated difference of dendritic arborization was detected in neither males nor females. The quantification of spines or synapses and cellular electrophysiology are still on-going. First signals point to an imbalance between excitation and inhibition as a cause of the female autism-like behavior in Ambra1+/- mice.||de