Myelin Proteolipid Protein Complexes with  v Integrin and AMPA Receptors In Vivo and Regulates AMPA-Dependent Oligodendrocyte Progenitor Cell Migration through the Modulation of Cell-Surface GluR2 Expression

Abstract

In previous studies, stimulation of ionotropic AMPA/kainate glutamate receptors on cultured oligodendrocyte cells induced the formation of a signaling complex that includes the AMPA receptor, integrins, calcium-binding proteins, and, surprisingly, the myelin proteolipid protein (PLP). AMPA stimulation of cultured oligodendrocyte progenitor cells (OPCs) also caused an increase in OPC migration. The current studies focused primarily on the formation of the PLP-␣v integrin-AMPA receptor complex in vivo and whether complex formation impacts OPC migration in the brain. We found that in wild-type cerebellum, PLP associates with ␣v integrin and the calciumimpermeable GluR2 subunit of the AMPA receptor, but in mice lacking PLP, ␣v integrin did not associate with GluR2. Live imaging studies of OPC migration in ex vivo cerebellar slices demonstrated altered OPC migratory responses to neurotransmitter stimulation in the absence of PLP and GluR2 or when ␣v integrin levels were reduced. Chemotaxis assays of purified OPCs revealed that AMPA stimulation was neither attractive nor repulsive but clearly increased the migration rate of wild-type but not PLP null OPCs. AMPA receptor stimulation of wild-type OPCs caused decreased cell-surface expression of the GluR2 AMPA receptor subunit and increased intracellular Ca 2ϩ signaling, whereas PLP null OPCs did not reduce GluR2 at the cell surface or increase Ca 2ϩ signaling in response to AMPA treatment. Together, these studies demonstrate that PLP is critical for OPC responses to glutamate signaling and has important implications for OPC responses when levels of glutamate are high in the extracellular space, such as following demyelination.

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

“…The function of PLP1 has not been fully established. However, PLP1 has been implicated in both OPC migration 26 and as a bridge between the membrane and cytoskeleton. 66 It is possible that, in the absence of PLP1, cell processes become insensitive to stimuli that would normally trigger them to extend.…”

“…[19][20][21][22][23] PLP1's strong cell-type specificity, abundance in myelin, and inter-species conservation all suggest that it fills an indispensable role in oligodendrocyte and myelin biology. However, PLP1's function in oligodendrocytes and myelin has only recently begun to be elucidated [24][25][26][27] and is still very much in question. As a result, there is no current consensus on the pathogenic processes by which PLP1 mutations cause PMD.…”

“…This surfeit and variety of human mutations suggest that multiple pathogenic processes could be responsible for the diverse manifestations of PMD. In prior literature, five possible molecular defects have been ascribed to certain PLP1 mutations: reduced expression, overexpression, 38 direct disruption of protein functional domains, 26 protein mistrafficking, 25,39,40 and protein misfolding leading to endoplasmic reticulum (ER) stress. 38,[41][42][43] The occurrence of these defects individually or in combination most likely accounts for much of the clinical heterogeneity observed in PMD.…”

The effect of dexmedetomidine on GluR2 and NR2B expression of cortical neurons after cerebral ischemia-reperfusion in rats

“…Neural injury decreases GluR2 expression and thus elevates Calcium ion influx. After ischemia or excitotoxicity, GluR2 expression is decreased in survival neurons [20]. NR1 represents a basic functional unit of NMDA receptor, while NR2 is of great importance for regulatory function of NMDA receptor, which is correlated with neuronal excitotoxicity, neuronal injury after brain ischemia-reperfusion [21].…”

Intertwining extracellular nucleotides and their receptors with Ca2+in determining adult neural stem cell survival, proliferation and final fate

“…Several studies have later addressed the importance of Ca 2þ signalling in process extension and OPC migration [58][59][60][61][62], in their differentiation, myelination and re-myelination capacity [63 -66], and in retraction of membrane sheaths and cell death in mature mouse oligodendrocytes [67].…”