Venue: Centre Broca, Carlsson room N3
Tereza Smejkalová
Czech Academy of Sciences, Institute of Physiology
Prague, Czechia
She will be visiting IINS on the 16th and most of the 17th. Please feel free to contact Mario Carta (IINS) if you would like to chat with her:
Title
Synaptic phenotypes of disease-associated variants in NMDA receptor genes
Abstract
NMDA receptors, encoded by GRIN genes, are ionotropic glutamate receptors important for synaptic plasticity and CNS development. Rare or de-novo variants in GRIN genes have been identified in patients with complex neurodevelopmental disorders but the disease mechanisms involved are not well understood and treatment options remain limited. Recent years saw tremendous progress in the understanding of GRIN gene-related disorders in terms of altered receptor function. The next hurdle will be to learn how disease-associated GRIN gene variants influence synaptic transmission and circuit function, and how to restore NMDA receptor signaling in GRIN patients using pharmacological or genetic therapy. Using in-vitro patch-clamp electrophysiology approaches in heterologous expression models or native systems we find that synaptic phenotypes of patient GRIN2 gene variants likely involve altered contributions of different types of GluN2 subunits to synaptic signaling. Further, given the diversity of NMDA receptor subunit composition across different brain circuits, the synaptic phenotype of a given variant may be different at different synapse types, with implications for the overall loss-of-function or gain-of-function outcome at the circuit level. Lessons learned from GRIN gene-related disorders may provide more general insights into neurodevelopmental disorders or diversity.