Hellwig S, Hack I, Kowalski J, Brunne B, Jarowyj J, Unger A, Bock HH, Junghans D, Frotscher M.
Role for Reelin in neurotransmitter release.
J Neurosci. 2011 Feb 16;31(7):2352-60.
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This paper by Hellwig et al. provides evidence to support yet another function for reelin in the CNS: presynaptic neurotransmitter regulation. The authors demonstrate that absence of reelin results in alteration in proteins involved in presynaptic machinery. Specifically, organotypic hippocampal slice cultures obtained from reelin-deficient (reeler) mice have an increased number of synaptic vesicles in CA1 stratum radiatum and reduced SNAP-25 expression. These changes are rapidly reversed with exogenous reelin application, or, conversely, can be mimicked with the application of CR-50, a reelin function blocking antibody. Surprisingly, no changes in vesicle number or SNAP-25 are seen in mouse knockouts of either the two reelin receptors (ApoER2 and VLDLR) or the intracellular adaptor protein, Dab1. This strongly suggests that reelin acts through a novel mechanism distinct from its well-known signaling ability via ApoER2 and VLDLR to influence presynaptic function. How might reelin be signaling? The authors used the RGD motif-containing integrin inhibitor peptide cyclo(Arg Gly-Asp-D-Phe-Val) on wild-typeT hippocampal organotypic slices to mimic the reeler phenotype of increased synaptic vesicles. Furthermore, the RGD peptide can effectively block the aforementioned reelin-dependent recovery of synaptic vesicle number in reeler slice cultures.
These results are not only the first to demonstrate a presynaptic role for reelin, but also the first to show a physiologic effect of reelin signaling that is ApoER2- and VLDLR-independent. Furthermore, they may shed light on the association of reelin to integrins, a connection that has been known for some time but misunderstood. This new role of reelin may represent a model for reelin processing by which signaling fragments with specific functional domains can interact either through the ApoER2 or VLDLR receptor system or through integrin-mediated presynaptic modulation to affect synaptic function. The current report underscores the importance of reelin in normal synaptic function and memory formation, and reveals the implications of Alzheimer’s disease-related alterations in reelin expression and processing. Furthermore, research from Joachim Herz and colleagues showing ApoE isoform-reelin interplay during hippocampal plasticity focuses attention on the importance of understanding the role of reelin in Alzheimer’s disease etiology and early-stage, short-term memory loss.