The specific goal of this research project is to examine the hypothesis that activity-dependent synaptic remodeling in development, and synaptic plasticity in the adult hippocampus, involve a family of molecules with well-known function in the immune system: MHC Class I genes (the HLA genes in humans).
We discovered neuronal MHC Class I (MHC I) mRNA expression unexpectedly in an unbiased PCR-based differential screen for genes regulated by the spontaneous neural activity present in the developing visual system (Corriveau et al, 1998). In the healthy brain, MHCI genes are dynamically regulated in neurons during development, and expression remains high in specific regions of adult brain, including hippocampus. mRNA for the Beta 2 microglobulin (β2m) light chain, required for cell surface expression of most MHC Class I proteins, is also present in neurons. In a preliminary search for potential Class I MHC receptors, subsets of neurons were also found to express mRNA for CD3 zeta (CD3ζ) (Corriveau et al, 1998), a required signaling component of immune receptors known to bind MHCI, including the T cell receptor (TCR). Recently, we have also discovered a novel unrecombined TCR transcript expressed in subsets of neurons (Syken and Shatz, 2003).
Genetic studies in my lab have revealed a functional requirement for Class I MHC in CNS development and plasticity (Huh et al, 2000). Experiments were performed in mice with a deletion of the gene encoding β2m, or in double mutant mice also lacking TAP1 (required for the loading of peptide into Class I MHC). In addition, CD3ζ knockout mice were studied. All mutants, but not wildtypes on the same genetic background, share significant defects in developmental remodeling of retinal ganglion cell (RGC) axons in the LGN that resemble deficits known to result from blocking neural activity directly. In addition, hippocampal synaptic plasticity in adult mutant mice is abnormal: long term potentiation (LTP) is enhanced and long term depression (LTD) is absent. The phenotypes of all these mice are consistent with the hypothesis that neuronal MHC Class I proteins, possibly signaling via a CD3ζ-containing Class I MHC receptor, are involved in synaptic plasticity in the hippocampus and structural regression of synapses during development. This purpose of this study is to learn more about how Class I MHC functions in the normal, uninjured CNS
Through this study, we plan to learn more about the distribution and function of Class I MHC in the normal mammalian CNS. In the clinical context, however, it should be noted that the presence of MHC1 in neurons also suggests new approaches to the study and treatment of neurological disorders, including and beyond those with known or suspected autoimmune components. For example, the molecular diversity implied by complex expression of various Class I MHC family members could help to explain the selective vulnerability of subsets of neurons in neurodegenerative disorders such as Parkinson's or ALS in view of the fact that nigral neurons and motoneurons express MHC Class I (see Boulanger et al, 2001).
A number of diseases are known to be linked genetically to MHC1 (HLA in humans) including multiple sclerosis, ALS, certain ataxias, narcolepsy, Parkinson's, dyslexia, autism, and schizophrenia. Perhaps even more provocative, it is well known that cytokines can upregulate MHC Class I cell surface expression in neurons, implying that dysregulation of normal MHCI expression might occur in viral infections where cytokine levels are often high. To what extent Class I MHC expression contributes to the cause or course of these disorders is currently unknown (see Darnell, 1998). It is clearly essential to learn more about this gene family, both in normal function and in dysfunction of the CNS.