Rasopathies are genetic disorders often associated with developmental delay and intellectual disability. Noonan syndrome (NS) is one of the most common Rasopathies, caused by mutations in PTPN11 in more than 50% of cases. In mammalian neurons, PTPN11 controls the trafficking of postsynaptic glutamate receptors. This process is disrupted in neurons expressing PTPN11 variants associated with Rasopathies and is thought to contribute to the cognitive impairments in Noonan syndrome. Recent work revealed presynaptic impairments upon expression of RASopathy-linked PTPN11 variants in Drosophila. However, the presynaptic role of PTPN11 has not yet been addressed in mammals. Here, we investigated membrane trafficking of synaptic vesicles in cultured mouse cortical neurons expressing Rasopathy-associated PTPN11D61Y variant. We observed a significantly smaller readily releasable and total recycling pool of synaptic vesicles. The drop in synaptic vesicle release competence was accompanied by a decreased rate of SV retrieval. Interestingly, the presynaptic phenotype was evident in mature (DIV21) but not in immature (DIV12) neurons. Thus, our data reveal importance of balanced PTPN11 activity for normal trafficking of neurotransmitter-filled synaptic vesicles in the presynaptic ending of mature neurons.

3rd Faculty of Medicine Charles University Prague Czech Republic

Department of Neurochemistry and Molecular Biology Leibniz Institute for Neurobiology Magdeburg Germany

Department of Psychiatry and Psychotherapy Universitätsklinikum Erlangen Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany

Institute for Pharmacology and Toxicology Medical Faculty Otto von Guericke University Magdeburg Germany

Institute of Human Genetics Medical Faculty University Hospital Magdeburg Otto Von Guericke University Magdeburg Germany

National Institute of Mental Health Klecany Czech Republic

RG Presynaptic Plasticity Leibniz Institute for Neurobiology Magdeburg Germany

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