Figure 7

Schematic diagram showing the possible effects of the reelin pathway in protection from CM. Reelin (RELN) is an extracellular matrix serine protease expressed in some neurons, such as GABAergic interneurons, which inhibit excitotoxic neurotransmission [45]. RELN that is secreted into the extracellular space acts by paracrine and autocrine mechanisms. RELN interacts with very low-density lipoprotein receptors (VLDLR) and apolipoprotein E type 2 receptors (ApoER2) leading to tyrosine phosphorylation of the adaptor protein Disabled-1 (DAB1) by the SRC family kinases (SRC) [42]. DAB1 activation, in turn, activates PI3K/Akt signalling, which has been implicated in neuronal migration during development and adulthood. In addition, phosphorylated DAB1 interacts with LIS1, a protein encoded by Pafah1b1, which associates with microtubules and modulates neuronal migration [46]. LIS1 may be required for regulating crucial steps of reelin-dependent neuronal positioning. In parallel, phosphorylated DAB1 inhibits glycogen synthase kinase 3β (GSK3β), a kinase known to phosphorylate Tau protein at multiple sites. Therefore, the activation of RELN pathway diminishes the level of hyperphosphorylated Tau protein, which is a biomarker of brain injury. In particular, hyperphosphorylated Tau protein is a component of the neurofibrillary tangles involved in Alzheimer's disease. Reln, Dab1 and Pafah1b1 were shown to be over-expressed in CM-R mice compared to CM-S mice. The activation of RELN signalling may inhibit excitotoxic neurotransmission and Tau phosphorylation, and may activate neurogenesis in CM-R mice. This may lead to diminished brain injury and to increased brain injury repair. Solid arrows represent influences on the activity of proteins or physiological mechanisms. Dashed arrows represent impaired effects on the activity of proteins or physiological mechanisms. Negative signs indicate inhibition, and positive signs indicate activation.