The role of NG2-LNS-domain-mediated glia-to-neuron signaling in neuronal synapse formation and function

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The present proposal is based in our recent discovery of a novel and functionally important mechanism by which glia cells modulate synapse and neuronal network properties. We found that Laminin G/Neurexin/Sex hormone-binding Globulin (LNS) domains of the glial protein NG2 act as potent modulators of glutamatergic neuronal synapses in the somatosensory cortex by regulating glutamate receptor kinetics and LTP. In view on this finding and the fact that LNS-domains are typical components of synaptic cell adhesion proteins, we propose here to combine the expertise of two laboratories (Trotter - cell biology, glial cells, NG2 biology; Brose - biochemistry, electrophysiology, synaptogenesis and synapse function) to study the exact mechanisms by which the NG2 LNS domains alter synapse formation and synaptic signaling. We plan to characterize the effect of NG2 LNS domains on the morphology and function of defined synapse subtypes and neuronal subpopulations. Importantly, we plan to identify the neuronal interaction partner(s) of the NG2 LNS domains that mediate their modulatory effect on neurons. In this regard, we will initially focus on CD166, a candidate NG2 LNS receptor that we jointly identified by affinity chromatography. We will study the functional relevance of the interaction between NG2 LNS and CD166, which will include the generation of mutant mouse models with altered or eliminated CD166 function. Finally, we will expand our systematic search for NG2 LNS receptors using biochemical and mass spectrometric approaches. We expect that our study will provide detailed insights into the molecular and cellular mechanisms by which NG2 LNS domains regulate synapses and neuronal microcircuits. This will not only reveal the mechanistic molecular and cellular intricacies of a novel and functionally highly relevant regulatory process in brain development and function, but may ultimately also reveal key links between this novel regulatory principle of NG2 LNS action and brain disease.