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Neurosci."],"published-print":{"date-parts":[[2020,11,18]]},"abstract":"<jats:p>Abnormalities in interactions between sensory neurons and Schwann cells (SCs) may result in heightened pain processing and chronic pain states. We previously reported that SCs express the NMDA receptor (NMDA-R), which activates cell signaling in response to glutamate and specific protein ligands, such as tissue-type plasminogen activator. Herein, we genetically targeted<jats:italic>grin1<\/jats:italic>encoding the essential GluN1 NMDA-R subunit, conditionally in SCs, to create a novel mouse model in which SCs are NMDA-R-deficient (GluN1\u2013 mice). These mice demonstrated increased sensitivity to light touch, pinprick, and thermal hyperalgesia in the absence of injury, without associated changes in motor function. Ultrastructural analysis of adult sciatic nerve in GluN1\u2013 mice revealed increases in the density of A\u03b4 fibers and Remak bundles and a decrease in the density of A\u03b2 fibers, without altered<jats:italic>g<\/jats:italic>-ratios. Abnormalities in adult Remak bundle ultrastructure were also present including aberrant C-fiber ensheathment, distances between axons, and increased poly-axonal pockets. Developmental and post radial sorting defects contributed to altered nerve fiber densities in adult. Uninjured sciatic nerves in GluN1\u2013 mice did not demonstrate an increase in neuroinflammatory infiltrates. Transcriptome profiling of dorsal root ganglia (DRGs) revealed 138 differentially regulated genes in GluN1\u2013 mice. One third of the regulated genes are known to be involved in pain processing, including<jats:italic>sprr1a<\/jats:italic>,<jats:italic>npy<\/jats:italic>,<jats:italic>fgf3<\/jats:italic>,<jats:italic>atf3<\/jats:italic>, and<jats:italic>cckbr<\/jats:italic>, which were significantly increased. The intraepidermal nerve fiber density (IENFD) was significantly decreased in the skin of GluN1\u2013 mice. Collectively, these findings demonstrate that SC NMDA-R is essential for normal PNS development and for preventing development of pain states.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>Chronic unremitting pain is a prevalent medical condition; however, the molecular mechanisms that underlie heightened pain processing remain incompletely understood. Emerging data suggest that abnormalities in Schwann cells (SCs) may cause neuropathic pain. We established a novel mouse model for small fiber neuropathy (SFN) in which<jats:italic>grin1<\/jats:italic>, the gene that encodes the NMDA receptor (NMDA-R) GluN1 subunit, is deleted in SCs. These mice demonstrate hypersensitivity in pain processing in the absence of nerve injury. Changes in the density of intraepidermal small fibers, the ultrastructure of Remak bundles, and the transcriptome of dorsal root ganglia (DRGs) provide possible explanations for the increase in pain processing. Our results support the hypothesis that abnormalities in communication between sensory nerve fibers and SCs may result in pain states.<\/jats:p>","DOI":"10.1523\/jneurosci.0663-20.2020","type":"journal-article","created":{"date-parts":[[2020,10,13]],"date-time":"2020-10-13T21:56:11Z","timestamp":1602626171000},"page":"9121-9136","source":"Crossref","is-referenced-by-count":28,"title":["Deletion of the Gene Encoding the NMDA Receptor GluN1 Subunit in Schwann Cells Causes Ultrastructural Changes in Remak Bundles and Hypersensitivity in Pain Processing"],"prefix":"10.1523","volume":"40","author":[{"given":"Coralie","family":"Brifault","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haylie","family":"Romero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Van-Enoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don","family":"Pizzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pardis","family":"Azmoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"HyoJun","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanond","family":"Nasamran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven L.","family":"Gonias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy M.","family":"Campana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2020,10,13]]},"reference":[{"key":"2023041803441567000_40.47.9121.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax6452"},{"key":"2023041803441567000_40.47.9121.2","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2014-309730"},{"key":"2023041803441567000_40.47.9121.3","unstructured":"Asbury AK (1970) The histogenesis of phagocytes during Wallerian degeneration: Radio-autographic observations. 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