Although there has been evidence for cross-talk between the immune and nervous systems for years, the idea that immune molecules have non-immune functions in the normal developing nervous system has only recently gained credence. This idea is based on observations that the primary mediators of the adaptive immune response, major histocompatibility complex class I (MHCI) molecules, are expressed in the brain where they mediate activity-dependent refinement of connections. MHCI molecules are also attractive candidates for molecular mediators of the effects of an abnormal or strong immune response on the developing brain, which has been implicated in the pathogenesis of several neurodevelopmental disorders, including autism and schizophrenia. The central goal of this proposal is to determine the function of MHCI during the initial establishment of cortical connections, a comparable developmental stage to the time of the immune challenge that may predispose humans toward neurodevelopmental disorders. Using immunocyto- and histochemistry, electron microscopy, cell and slice culture and transfection, a novel long-term imaging assay, and whole-cell patch-clamp recording, we will address the following Aims. (1) To determine the localization of MHCI molecules in vivo and in vitro during cortical development. (2) To test the hypothesis that MHCI molecules regulate the initial establishment and function of cortical connections in vivo and in vitro. (3) To determine whether MHCI molecules negatively regulate the establishment of cortical connections by inhibiting synapse formation, increasing synapse elimination, or both. (4) To test the hypothesis that MHCI molecules act through natural killer cell receptors to negatively regulate the establishment of cortical connections. Results from this proposal should reveal novel functions of MHCI in the typically developing brain, as well as potential mechanisms for how they might contribute to neurodevelopmental disorders.
Although a wide range of environmental stimuli have been proposed to play a role in the pathogenesis of neurodevelopmental disorders including autism and schizophrenia, many of these stimuli have in common the ability to alter immune function. Since MHCI molecules initiate and mediate the immune response 9 and are present in the brain 10, it is entirely possible that changes in expression of MHCI in the developing brain caused by environmental insults contribute to the cellular changes that cause these disorders. The central goal of this proposal is to determine the function of MHCI proteins during the initial formation of connections in the early postnatal brain, a comparable developmental stage to the time of the immune challenge proposed to predispose humans toward neurodevelopmental disorders.
|Estes, Myka L; McAllister, A Kimberley (2016) Maternal immune activation: Implications for neuropsychiatric disorders. Science 353:772-7|
|Estes, Myka L; McAllister, A Kimberley (2016) IMMUNOLOGY. Maternal TH17 cells take a toll on baby's brain. Science 351:919-20|
|Estes, Myka L; McAllister, A Kimberley (2015) Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci 16:469-86|
|Estes, Myka L; McAllister, A Kimberley (2014) Alterations in immune cells and mediators in the brain: it's not always neuroinflammation! Brain Pathol 24:623-30|
|McAllister, A Kimberley (2014) Major histocompatibility complex I in brain development and schizophrenia. Biol Psychiatry 75:262-8|
|Elmer, Bradford M; Estes, Myka L; Barrow, Stephanie L et al. (2013) MHCI requires MEF2 transcription factors to negatively regulate synapse density during development and in disease. J Neurosci 33:13791-804|
|Garay, Paula A; Hsiao, Elaine Y; Patterson, Paul H et al. (2013) Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development. Brain Behav Immun 31:54-68|
|McAllister, A Kimberley; Patterson, Paul H (2012) Introduction to special issue on neuroimmunology in brain development and disease. Dev Neurobiol 72:1269-71|
|Elmer, Bradford M; McAllister, A Kimberley (2012) Major histocompatibility complex class I proteins in brain development and plasticity. Trends Neurosci 35:660-70|
|Needleman, Leigh A; McAllister, A Kimberley (2012) The major histocompatibility complex and autism spectrum disorder. Dev Neurobiol 72:1288-301|
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