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MHCI Molecules
Although it has long been dogma that the healthy CNS is “immune-privileged,” a paradigm shift in the field of neuroimmunology has occurred in the last 10 years due in large part to the discovery that classical immune molecules, such as cytokines, complement, and major histocompatibility complex I (MHCI) proteins are expressed in the developing and adult brain. MHCI plays a wide range of important roles in development and plasticity and may also contribute to the pathogenesis of neurodevelopmental disorders, including schizophrenia (SZ) and autism spectrum disorder (ASD). Despite accumulating evidence for the importance of MHCI in the brain, almost nothing is known about the cellular and molecular mechanisms that mediate its effects.
Recently, we discovered that MHCI molecules are present both pre- and postsynaptically at synapses on neurons in the visual cortex throughout postnatal development and into adulthood (Needleman et al. 2010). Cell surface presentation of MHCI is tightly regulated by synaptic activity and it potently limits synapse strength and density, as well as the balance of excitation to inhibition, between young cortical neurons in vivo and in vitro (Glynn et al. 2011). MHCI molecules are one of only a few kinds of proteins that limit the ability of a neuron to form synapses, as well as cause existing synapses to be eliminated. Studying the mechanisms of MHCI function may thereby reveal fundamental principles of this relatively new and understudied, negative regulation of synapse density in the early postnatal brain.
Estes & McAllister (2015) doi: 10.1038/nrn3978
To that end, there is a major effort in my lab to determine how MHCI controls synapse density. Since it does not require the MHC receptor PirB for this effect, we have employed mass spec to identify novel MHCI binding partners and recently obtained a list of potential MHCI binding proteins that we are now pursuing for their ability to mediate the effects of MHCI on synaptic strength and synapse density. In addition, we are currently determining the downstream effectors of MHCI in regulating synapse density and have found that p38 and calcineurin, but not Erk5, mediate MHCI-induced activation of MEF2 transcription factors to cause synapse elimination. How MHCI activates these signaling cascades in neurons is the focus of intense effort in my lab. Remarkably, the novel binding partners for MHCI and its downstream signaling converge on a common molecular pathway at the synapse implicated in ASD (neurexin-neuroligin-shank-FMRP-MEF2; Betancur et al. 2009), implying that this molecular pathway can be altered by both environmental insults (that alter neuronal MHCI levels) and genetic mutations that cause ASD.
Finally, In addition to its expected postsynaptic localization, MHCI is also abundant in the axon and presynaptic terminal of cortical neurons. However, there are no reports to date of any function for axonal or presynaptic MHCI. Current efforts in the lab are focused on developing novel approaches to address this important question.
Cytokines and their receptors
Our lab has also started experiments to determine the upstream signaling cascades that regulate MHCI expression in neurons, focusing on cytokines like interleukin-1. As the neuroscience field has started to accept that immune dysregulation contributes to brain development and function, there has been a widespread assumption that it must be neural inflammation that is involved. However, our results are more consistent with the idea that changes in signaling downstream of immune molecules on neurons may mediate these effects.
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