The intracellular domain of major histocompatibility class-I proteins is essential for maintaining excitatory spine density and synaptic ultrastructure in the brain

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 a MHC-I protein, to resolve underlying mechanisms that explains its function in the brain. We demonstrate that Y321F mutation of the conserved cytoplasmic tyrosine-based endocytosis motif YXX & phi; in MHC-I affects spine density and synaptic structure without affecting neuronal complexity in the hippocampus, a region of the brain intimately involved in learning and memory. Furthermore, the impact of the Y321F substitution phenocopies MHC-I knock-out (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 a previously undescribed yet essential role in the regulation of synaptic plasticity.

Automated summary

MHC-I proteins are expressed in neurons and regulate synaptic plasticity, but their mechanisms in the CNS are still unknown. This study provides the first structural analysis of a MHC-I protein, revealing its underlying mechanisms in the brain. The Y321F mutation of MHC-I affects spine density and synaptic structure in the hippocampus, without impacting neuronal complexity, and mimics the phenotype of MHC-I knock-out animals, suggesting a crucial role of reverse, outside-in signaling events in regulating synaptic plasticity.