Function of the synaptic cell adhesion protein neurexin-3 in human neurons

• Applicant: Christian Thome, Ph.D.
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Molecular Biology and Physiology of Neurons and Glial Cells ; Molecular and Cellular Neurology and Neuropathology
• Term: from 2021 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458054460

Synapses establish complex and adaptive networks by linking billions of individual neurons. Signal processing within these circuits is thought to create the functions of perception, thought, memory, and behavior. Many neuropsychiatric disorders are believed to arise from the dysregulation of synaptic transmission. Indeed, mutations in genes that encode for synaptic proteins were found to predispose for diseases like autism, schizophrenia, and Tourette syndrome. The causal relations between molecular-cellular processes and systemic dysfunctions are, however, poorly understood. The proposed study will use a novel, stem cell-based approach to investigate the physiological role of the synaptic protein neurexin-3 in neuronal transmission and in disease-related malfunctions. Neurexins are transmembrane proteins that link the pre- and postsynaptic compartments of synapses. In humans, mutations in all three isoforms of these synaptic adhesion molecules confer high risk to develop autism spectrum disorders, and the neurexin-3 gene has additionally been associated with drug addiction and obesity. Until now, the physiological role of neurexin-3 mutations in synaptic function has only been studied using animal models where its deletion causes severely impaired synaptic transmission. However, recent evidence from the laboratories involved in this proposal shows that neurexin mutations have different effects in human cells, limiting the transferability of mouse models to the human context. We, therefore, want to clarify the role of neurexin-3 in a human cell system. The proposed study makes use of a method established in the Wernig lab. Human neurons derived from induced pluripotent stem cells (iPS) are differentiated into excitatory and inhibitory neurons and recombined to generate mature cultured networks including glia. In this system, we can study the effects of conditional neurexin-3 deficiency in otherwise genetically identical cells. We will study the functional deficits at excitatory and inhibitory synapses using patch-clamp recordings. In addition, we will gather information on neuronal maturation, synapse development, and cell morphology by immunohistochemistry and confocal imaging. Building upon previous data from the Wernig and Südhof labs we expect a clear phenotype that will provide significant insights into the role of neurexin-3 in human neurons. The proposed work will thus not only expand our knowledge about this protein family but also aid our understanding of mutation-associated disorders and synaptic function in general.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Marius Wernig, Ph.D.