Multilevel Phenotyping of Mouse Models for Neurodevelopmental Disorders

The underlying disease mechanisms of neurodevelopmental disorders (NDDs) have been investigated in this thesis by applying a multilevel phenotyping approach of mouse models. We generated and characterized several valid mouse models for NDDs, namely Stxbp1+/- mice (on four different genetic backgrounds), Stxbp1+/-Snap25+/- mice, Stxbp1+/+Snap25+/- mice and Dpp10 transgenic mice. The underlying disease mechanisms have been investigated on the cellular, network, system and behavioural level. In Chapter 2, we studied how heterozygous mutations in the STXBP1 gene leads to early infantile epileptic encephalopathy. We showed that decreased protein stability, STXBP1 haploinsufficiency and imbalanced excitation in the cortex explain STXBP1-encephalopathy and that Stxbp1+/- mice represent a valid mouse model with construct, face and predictive validity. In Chapter 3, we investigated the phenotypic diversity of SNAREopathies by studying gene interactions between two SNARE genes, namely Stxbp1 and Snap25. This study demonstrated that haploinsufficiency at two interacting loci at cellular and/or network level can explain deviation and severity of the epileptic phenotype in double Stxbp1/Snap25 mice and that atypical cortical development of GABA-ergic inhibition can contribute to the cognitive and behavioural impairments. Findings from this chapter provide a proof of concept for how modifying genes in the patient genome may enhance phenotypic diversity in human patient population. In Chapter 4, we studied the link between aberrant behavioural phenotypes observed in Dpp10null mice generated using insertional mutagenesis, and the functional consequences of gene inactivation on the cellular level. We showed that lack of Dpp10 expression affects inhibitory neuron branching and synapse number, neuronal excitability and leads to acoustic hypersensitivity, hyperactivity and impaired working memory in mice. Taken together, the data acquired in this thesis provide novel insights into the neurobiological basis of NDDs and their phenotypic diversity using transgenic mouse models.