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

Maciej J. Lazarczyk, Brett A. Eyford, Merina Varghese, Hitesh Arora, Lonna Munro, Tahia Warda, Cheryl G. Pfeifer, Allison Sowa, Daniel R. Dickstein, Timothy Rumbell, Wilfred A. Jefferies, Dara L. Dickstein

Research output: Contribution to journalArticlepeer-review

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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 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 YXXΦ 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.

Original languageEnglish
Article number6448
JournalScientific Reports
Volume13
Issue number1
DOIs
StatePublished - Dec 2023

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