AMPA receptor complexes as adaptive regulators of synaptic strength

• Applicant: Dr. Igor Delvendahl
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Anatomy and Physiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 535030493

Our brain comprises an intricate network of billions of neurons connected by an even greater number of synapses. Transmission at chemical synapses forms an indispensable basis for the function of the nervous system. Synapses are highly complex structures that allow precise and rapid transfer of information between neurons. At the molecular level, synapses are highly dynamic and undergo remodelling that is critical for several aspects of brain physiology. Despite detailed insights into the structure and function of synaptic molecules, the interactions that lead to the dynamic and adaptive behaviour of synapses remain enigmatic. AMPA-type glutamate receptors (AMPARs) are central to excitatory synaptic transmission, and their importance for synaptic plasticity is well established. However, the dynamic behaviour and molecular interactions of AMPARs are not well understood. Based on recent evidence, extracellular, secreted proteins that interact with AMPARs emerge as intriguing candidates for supporting the adaptive regulation of synaptic function. These include neuronal pentraxins (NPTX), conserved glycoproteins that stabilize synaptic AMPARs. NPTX1 specifically associates with the GluA4 AMPAR subunit, which is important for fast and precise synaptic transmission and is particularly expressed in the cerebellum. This project will combine state-of-the-art proteomics with functional and behavioural analyses to investigate the interaction between GluA4 AMPARs and NPTX1. Affinity purification-based proteomics combined with knockout mouse models will reveal the molecular composition and interaction landscape of GluA4 complexes. Electrophysiological experiments will comprehensively characterize the functional role of NPTX1 in the cerebellum from the single synapse level to behaviour. The results will elucidate the architecture of the GluA4-containing AMPAR proteome and uncover the role of NPTX1 for synaptic transmission and cerebellar function. Characterising how AMPARs and associated proteins enable adaptive behaviour of synapses is fundamental to a better understanding of neural function and the pathophysiology of neurological disorders, and may pave the way for new therapeutic approaches.

• DFG Programme: Research Grants