Neuronal MHC Class I Expression and Function in Synapse Remodeling

Carla J. Shatz, Ph.D.

Stanford University School of Medicine

Funded in March, 2004: $300000 for 4 years
LAY SUMMARY . ABSTRACT . SELECTED PUBLICATIONS .

LAY SUMMARY

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Immune System Molecules May Play a Key Role in Developing Brain Cell Connections

Harvard University researchers’ recent studies of how brain cells form visual system connections revealed an unexpected finding: a family of immune system molecules appears to play a critical role in directing the process.  The molecule family is called major histocompatability class I (MHC I).  In the immune system, these molecules identify and trap an invading pathogen and display it to certain innate immune cells so that they can orchestrate an immune attack.  Now, it turns out, MHC I molecules are apparently involved in the development of synapses that enable brain cells to communicate with one another.

According to the researchers, it is essential to learn more about this gene family in both normal function and dysfunction of the central nervous system.  The investigators hypothesize that MHC I genes are involved in modeling brain cell synapses during brain development, and re-modeling of some synapses (called “plasticity”) that can occur throughout life.

Their preliminary evidence suggests that subsets of brain cells have a receptor on their surface that binds to these MHC I molecules.  The researchers plan to investigate the functions of this class of molecules in normal brain development and to determine how these brain cell subsets also may be more vulnerable to degenerative brain diseases such as Alzheimer’s and Parkinson’s disease. 

To explore the role in the brain of these previously identified “immune system” molecules, the researchers will undertake three studies in mice.  First, they will identify the family members of the MHC I genes involved in the central nervous system, and determine whether these genes are distinct from classical MHC I genes found in the immune system.  Next, the investigators will examine whether a single neuron expresses multiple MHC I genes, and whether certain MHC I genes are restricted to certain types of brain cells. Then, the researchers will explore the role of the MHC I genes in growth and termination of brain cell synapses in the visual system.  They will compare normal mice to those with MHC I mutations to explore whether the mutant mice have unstable MHC I expression, or lack MHC I signaling, which prevents nerve cell axons from projecting from the retina to the thalamus in the precise way needed for producing visual function. 

Significance:  Through this three-step animal study, the investigators will determine whether MHC I molecules function at neuronal synapses and participate in synapse formation and stabilization.  If so, the research should provide new information on how MHC I molecules function normally in the central nervous system, and also how these molecules may participate in degenerative diseases that destroy nerve cell connections.

ABSTRACT

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Neuronal MHC Class I Expression and Function in Synapse Remodeling

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.

SELECTED PUBLICATIONS

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Goddard C.A., Butts D.A., and Shatz C.J.  Regulation of CNS synapses by neuronal MHC Class I.  Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6828-33.