Role of AMPAR gating kinetics in synapse function and information processing

• Applicant: Professor Dr. Jakob von Engelhardt
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545237594

AMPAR-type ionotropic glutamate receptors (AMPARs) are key in fast-excitatory neurotransmission and are crucial in synaptic plasticity and neurological disorders. Their number and function are influenced by their core subunit composition and associated accessory proteins, which control synaptic localization, number, and gating properties. While AMPAR synaptic trafficking is well-studied, the regulation of their gating kinetics and its physiological role is less understood. This study will explore the impact of new human mutations in AMPAR GluA2 and CKAMP (shisa) family of accessory proteins, linked to cognitive and motor disabilities, on AMPAR function. The first part focuses on a novel de-novo GluA2 mutation, preliminarily shown to increase AMPAR desensitization, potentially limiting in vivo currents. This differs from the enhancing effects of other human GluA2 mutations studied so far, and offers a unique research tool. The second part investigates human missense mutations in a member of the CKAMP family. Our study will use heterologous cells, patient iPSC-derived neurons, and transgenic mice to understand the molecular and physiological impacts of these mutations on AMPAR function. In vivo analysis of neuron activity in mice harboring the mutations will give insights into the relevance of specific AMPAR gating properties, and particularly of desensitization, in information processing. This integrated approach aims to provide a comprehensive understanding of mutations' mechanisms. Collectively, this study will yield new insights into AMPAR functions in health and disease, potentially guiding long-term treatment strategies for AMPAR-associated disorders.

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Professorin Yael Stern-Bach, Ph.D.