Characterization and interventional strategies in novel transgenic rat models of autism spectrum disorders

Abstract

Autism spectrum disorders (ASD) are neurodevelopmental disorders with repertoires of symptoms such as social interaction deficits, restrictive/repetitive behaviors and language deficits. ASD’s are also associated with co-morbid symptoms like intellectual disability, anxiety & epilepsy. These disorders are highly heritable, penetrant and heterogeneous in nature with strong genetic basis. There are currently no effective pharmacological treatments for ASD or ID, due in part to a lack of understanding of the pathophysiology of these disorders. Single-gene mutations account for a large proportion of cases where individuals present with ASD and co-occurring intellectual disability. Mutations in genes coding for synaptic proteins such as cell adhesion molecules, translational regulators, ion channels etc., have been identified by genome wide association studies in ASD patients. In this thesis I have evaluated the altered behavioral profile of novel transgenic rat models of synaptopathies which are implicated in ASD. These rat models include mutation in genes coding for post synaptic proteins like cyclin dependant kinase like 5 (CDKL5), synaptic Ras GTPase (SYNGAP), phosphatase and tensin homolog (PTEN) and neuroligin 3 (NLGN3). This study for the first time provides evidence for aberrant behaviors in the novel transgenic rat models of synaptopathies across a range of social, cognitive, sensory-motor, and emotional domains. Further, this study explores interventional strategies such as Insulin like growth factor 1-3 (IGF) to rescue specific behavioral phenotypes in Nlgn3-/y rats. Mutations leading to synaptopathy might have commonalities and differences with respect to their behavioral phenotypes. In four genetically distinct models of synaptopathies, this work emphasizes the convergence and divergence among the reported behavioral features. This implies that despite the genetic heterogeneity, there may be patho-physiologies which could be shared and this knowledge may be utilized to formulate treatments that are effective for a wider range of ASD patients. Moreover, this work highlights novel avenues for behavioral research in ASD models, with respect to mechanistic validity, often needed in translational research.