Reelin and Gastrin-Releasing Peptide Modulate Itch in the Superficial Dorsal Horn of the Spinal Cord
- Mavilian, Christine Michelle
- Advisor(s): Phelps, Patricia E.
Abstract
The Reelin-signaling pathway mediates a vital role in correctly positioning neurons within the dorsal horn of the spinal cord. Reelin binds to its two receptors, Apolipoprotein E receptor 2 (Apoer 2) and Very-low-density receptor (Vldlr) and induces phosphorylation of its intracellular adaptor protein Disabled-1 (Dab1) by Src family kinases. Dab1 phosphorylation activates a downstream signaling cascade that influences neuronal migration and positioning within the central nervous system during embryonic development (D’Arcangelo et.al., 1999). Previous studies have shown that mutations in Reelin and Dab1 induce alterations in nociceptive processing. Reeler and dab1 mutants display thermal hyperalgesia and decreased sensitivity to mechanical stimulation (Akopians et. al., 2008; Villeda et. al., 2006). In addition to nociceptive processing, the Reelin-signaling pathway may also influence pruritogenic behavior. Itch, like pain, is a major somatic sensation relayed via the somatosensory pathway system (Jeffrey et. al., 2011). Gastrin-Releasing Peptide (GRP) is a neurotransmitter involved in transmitting itch information and is abundantly expressed in the superficial dorsal horn (Solorzano et al., 2015, Barry et al., 2020). However, the molecular mechanisms downstream of GRP that underlie itching behavior are still elusive. Therefore, the overall aim of this project is to determine whether the Reelin-signaling pathway mediates a role in pruritogenic behavior and whether GRP neurons are implicated in the reduced itching behavior of dab1-/- mice. Our preliminary data show that approximately 34% of GRP neurons co-express Reelin and that roughly 16% of Reelin-positive neurons co-express GRP. Unlike Reelin, Dab1-expressing neurons do not colocalize with GRP. We determined that Reelin-Lmx1b-GRP triple-labeled neurons are mispositioned above the IB4 band in Dab1-/--Grp mice and there are greater total number of GRP cells in Dab1-/--Grp compared to Dab1+/+-Grp mice . There are also more Reelin-Lmx1b-GRP triple-labeled neurons within the IB4 region of Dab1-/--Grp mice. Importantly, we discovered an abnormal expansion of the central area above the IB4 band in our mutant mice, which differs from previous findings of a dorsal shift and neuronal compaction of laminae I-II outer. The lateral compaction of the dorsal horn appears to be consistent with previous reports. Future studies will further investigate the relationship between Dab1 and GRP and the abnormal expansion of the central area above the IB4 band.