Synaptic Plasticity Conveyed by the Intracellular Domain of Major Histocompatibility Class-I Proteins

Abstract

Abstract Major histocompatibility complex class I (MHC-I) proteins are expressed in neurons, where they regulate synaptic plasticity. However, the mechanisms by which MHC-I functions in the CNS remains unknown. Here we describe the first structural analysis of MHC-I, to resolve underlying mechanisms that explains its function. We demonstrate that Y321F mutation of the conserved cytoplasmic tyrosine-based endocytosis motif YXXΦ in MHC-I affects spine density and synaptic structure without affecting neuronal complexity. Furthermore, the impact of the Y321F substitution phenocopies the MHC-I null animals, demonstrating that reverse, outside-in signalling events sensing the external environment is the major mechanism that conveys this information to the neuron and this has an essential role in the regulation of synaptic plasticity.