Reelin

9.1. Reelin and Its Receptors

Reelin is a secreted ECM glycoprotein that binds transmembrane receptors on neurons and activates tyrosine kinase signaling cascades89. Animals with mutations in Reelin (Reeler mice) strikingly display abnormal neuronal migration such that cortical neurons reverse their normal layering pattern90. Reelin signals through two main receptors, the very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2). Both of these receptors appear to signal through the disabled (Dab-1) signaling pathway to mediate Reelin's effects on neuronal migration91. In addition, there is evidence that Reelin can signal through a3p1 integrin-dependent pathways as well92.

9.2. Reelin's Role in Synaptogenesis

In addition to an effect on migration, studies have also linked Reelin to synapse formation in the hippocampus. Although hippocampal layering is largely unaffected in the Reeler mouse, defects are seen both in axonal pathfinding and synaptogenesis in the hippocampus93,94. Hippocampal entorhinal projections are topographically correct in Reeler mice, but more fibers make aberrant projections, there are fewer branches of entorhinal axons, and there is a nearly 50% reduction in the number of synapses at P2 and a 30% reduction at P1294. Also heterozygous Reeler mice exhibit a decrease of dendritic spine density on cortical and CA1 pyramidal neurons of the hippocampus95. It is difficult to verify if Reelin is playing a direct role in hippocampal synaptogenesis or if the reduction is due to poorly developed dendritic trees or the reduced branching and misrouting of the entorhinal projections. Multiple mechanisms for Reelin in synaptogenesis are likely because there are fewer synaptic varicosities per length of axon in Reeler mice94, Reelin is expressed in CNS synapses and affects synaptic properties96 as well as dendritic development97.

Another intriguing example of a possible role for Reelin in synaptogenesis comes from studies of the retina. Reelin is expressed by retinal ganglion cells, amacrine cells, and rod bipolar cells in the developing and adult retina98. Reelin is also strongly expressed in the synaptic inner plexiform layer of the retina and as this layer matures into its distinct ON/OFF sublaminae (see ref. 99 for review), Reelin becomes localized predominantly to the ON layer92. In the Reeler mouse, a subset of Reelin expressing rod bipolar cells terminate in the incorrect layer of the retina and do not synapse in the ON sublamina. Thus, Reelin may play a role in the establishment of appropriate synaptic circuitry in the retina perhaps by modulating the relative adhesiveness of proteins involved in synaptic specificity.

9.3. Reelin and Synaptic Maturation

Several studies suggest that Reelin affects synaptic functions via VLDL and apoER2 receptors which may induce mDab1 tyrosine phosphorylation and activation of nonreceptor tyrosine kinases of the Src family. This idea is supported by recent data on maturation of synapses in hippocampal cultures96. In this system, chronic blockade of the function of Reelin with antisense oligonucleotides or the function-blocking antibody prevented the decrease of NR1/2B-mediated whole-cell currents, which is a hallmark of synaptic maturation. Conversely, exogenously added recombinant Reelin accelerated the maturational changes in NMDA-evoked currents. Importantly, the change in NMDAR subunits was also blocked by chronic treatment with an inhibitor of the Src kinase signaling pathway or an antagonist of the LDL receptors, receptor associated protein96. Even stronger evidence supports a link between Reelin, apoER2, tyrosine phosphorylation of NMDA receptors, and long-term potentiation8. Thus, signaling via apoER2/VLDL receptors and tyrosine phosphorylation appeared to be critical in mediating effects of Reelin on synaptic functions. Whether the same mechanisms are operant during stabilization of nascent synapses remains to be investigated. The importance of the above-described findings is underscored by reduction of Reelin expression in psychotic patients and similarities in some cellular and synaptic abnormalities observed in these patients and Reeler mice.

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