Dissecting the function of Eps15 and Eps15R in the mammalian forebrain

• Applicant: Professorin Dr. Tanja Maritzen
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Molecular and Cellular Neurology and Neuropathology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 564631098

Brain function critically relies on the proper sorting of crucial membrane proteins. At the presynapse, synaptic vesicle proteins have to be retrieved from the membrane after neurotransmitter release to locally replenish the synaptic vesicle pool and thereby sustain neurotransmission. At the postsynapse, neurotransmitter receptors need to be dynamically inserted and removed from the membrane to enable synaptic plasticity and, thus, learning and memory. Consequently, sorting defects give rise to severe neurological diseases including epilepsy. The endocytic sorting of transmembrane proteins is often regulated by endocytic adaptor proteins, which link them to the endocytic machinery. The closely related proteins Eps15 and Eps15R are two such endocytic adaptors with vital functions in the mammalin brain as our preliminary studies reveal. Neuronal deletion of Eps15/Eps15R in mice causes growth delay, behavioral alterations, epileptic seizures and premature death consistent with potential synaptic sorting defects. In line with this, our imaging experiments reveal a surface accumulation of postsynaptic AMPA-type glutamate receptors upon loss of Eps15/Eps15R. In addition, the double knockout mice display neuronal layering defects and enlarged ventricles, the hallmark of congenital hydrocephalus, a major cause of childhood morbidity and mortality affecting 1 in 1000 live birth. These results clearly suggest additional roles of Eps15 and Eps15R beyond the synapse. Furthermore, via unbiased mass spectrometry-based interaction studies we have uncovered novel interaction partners of Eps15R suggesting a role in autophagy. To unravel the molecular mechanisms behind these diverse findings, we propose here (i) to dissect how Eps15/Eps15R facilitate the endocytosis of specific AMPA receptors at the molecular level and to analyze whether the loss of Eps15/Eps15R impacts postsynaptic plasticity; (ii) to investigate the role of Eps15 and Eps15R in presynaptic endocytosis and SV regeneration and to elucidate the organismic consequences of Eps15/Eps15R loss on basal neurotransmission, presynaptic plasticity and behaviour; (iii) to address how loss of Eps15/Eps15R might cause neuronal lamination defects and hydrocephalus; and (iv) to unravel whether Eps15R plays a role in the autophagy of endocytic components in mammalian neurons. With these lines of research and a combination of live cell imaging, super-resolution microscopy, biochemistry and electrophysiology we will address important questions in molecular neuroscience and cell biology and substantiate the paradigm that trafficking defects may underlie neurological diseases.

• DFG Programme: Research Grants