Developmental, brain region and cell type specific functions of the postsynaptic scaffold protein SAPAP4

• Applicant: Dr. Claudia Schob
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Biological Psychiatry ; Experimental Models for the Understanding of Nervous System Diseases ; Cognitive, Systems and Behavioural Neurobiology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 451510750

In humans, genetic variants of DLGAP1-4 have been linked with neuropsychiatric conditions, including autism spectrum disorder (ASD). While these findings implicate the encoded postsynaptic proteins, SAPAP1-4, in the etiology of neuropsychiatric conditions, underlying neurobiological mechanisms are largely unknown. In the past, I characterized constitutive Dlgap4 knockout mice to assess the contribution of SAPAP4 to these disorders. This study revealed that loss of SAPAP4 triggers profound behavioural abnormalities, including hyperactivity, insufficient motor coordination and learning as well as severe cognitive deficits combined with impaired vocal communication and social interaction, phenotypes that are at least in part reminiscent of ASD in humans. Behavioural alterations of SAPAP4-deficient mice are associated with dramatic changes in morphology, function and plasticity of excitatory synapses in the CA1 area of the hippocampus. These findings indicate that SAPAP4 is critical for the development of functional neuronal networks and that mutations in the corresponding human gene, DLGAP4, may cause deficits in social and cognitive functioning relevant to ASD-like neurodevelopmental disorders. Aim of this proposal is to characterize developmental, cell-type and brain region specfic functions of SAPAP4 to better understand its significance for cognition, social behaviour, activity as well as motor coordination and learning. I will establish several conditional Dlgap4 knockout mouse lines and assess animal phenotypes via various biochemical, morphological and behavioural assays. Also, I will test how missense mutations in DLGAP4 affect functional properties of SAPAP4. Results are anticipated to further provide deeper insight into postsynaptic mechanisms controlling activity-dependent plasticity of excitatory brain synapses and thus plasticity-related mammalian behaviours, such as cognition and social performances. Moreover, they shall enable us to better understand anatomical foundations and neuronal networks involved in distinct patterns of behaviour. Disruption of these mechanisms are assumed to contribute to neurodevelopmental and neuropsychiatric disorders in humans. In the long run, newly gained findings shall help to decode the pathophysiological basis of neuropsychiatric conditions and to develop adequate therapeutic concepts.

• DFG Programme: Research Grants