Background: NMDAR in myelinating oligodendrocytes have an important regulatory role (checkpoint) in preserving axonal energy balance and thus neuronal circuitry underlying e.g. higher brain functions.
Hypothesis: NMDAR1-AB, present in a large fraction of healthy individuals, affect this checkpoint upon access to the brain. This is relevant in conditions of CNS injury by affecting recovery from disease.
Strategy: We will generate and study novel murine models of autoimmune encephalitides as well as use conditional NMDAR1 KO mice.
Myelinating glia provide lactate to axons, which supports the generation of ATP required for fast spiking. Oligodendrocytes adjust the necessary number of glucose transporters (GLUT1) by N-methyl-d-aspartate receptor (NMDAR) signalling, presumably in response to axonal activity, which causes non-synaptic glutamate release by axons as a proxy of energy demands. Loss of oligodendroglial NMDAR in mutant mice does not prevent myelination but leads to axonal energy deficits and later widespread activation of microglia in white matter. This raises the intriguing possibility that naturally occurring NMDA receptor1 autoantibodies (NMDAR1-AB), found circulating in a significant fraction of healthy individuals (and intrathecally in patients with so-called “anti-NMDAR encephalitis”) affect oligodendroglial energy metabolism and axonal conduction properties when the blood-brain-barrier (BBB) is perturbed. We will immunize mice against NMDAR1, which by itself does not cause disease. Immunization will be performed in two encephalitis models: (1) Cnp-/- mice as prototype of genetically induced white matter inflammation and (2) mice with an inducible transgene for diphtheria toxin-mediated ablation of neurons, generating grey matter inflammation. Cell death will be controlled by dosing tamoxifen to mimic a human viral disease. We will further compare the behavioural and neuropathological phenotype of immunized mice that have or lack oligodendroglial NMDAR. This allows us to dissect cardinal features of “anti-NMDAR encephalitis”, e.g. synaptic dysfunction that we think causes psychosis-like symptoms, and putative oligodendroglial metabolic defects. We hypothesize that the presence of NMDAR1-AB represents an important checkpoint affecting the recovery from CNS injury. Since low grade inflammation is a common feature of various myelin disorders, we will also test in immunized Cnp-/- mice the hypothesis that pharmacological ablation of microglia supports the recovery from a vicious circle of degeneration and inflammation triggered by NMDAR1-AB.