IGF1 deficiency hinders myelination and creates a structure just like the ones seen in GSK3 over-expression and SZ consisting of brain atrophy, reduced myelination and cortical thickness, and increased neuronal density with no change in neuronal number. Reelin is another key signaling glycoprotein that interacts with a few of the same receptors, deacetylase inhibitor is secreted into extracellular matrix as apolipoprotein E, and helps organize embryonic and adult brain development and restoration. Reelin interacts with exactly the same signaling pathways as dopamine 2 receptors and can thus promote myelination and could indirectly hinder GSK3. Conversely, inhibition of reelin should reduce myelination and is demonstrated to impair mental functions. Reelin deficits are consistently observed in developmental disorders such as major depression, BD, SZ, and autism and such deficits can bring about the myelination deficits observed in these disorders. However, Latin extispicium reelin over-expression seems to reduce behavioral phenotypes associated with BD and SZ in animal models. Reelin is secreted by oligodendrocytes and their precursors and after youth, it’s also secreted by GABAergic interneurons during cortical layers II VI and hippocampus, and may help account for the co-occurrence of reelin and GABA deficits in psychiatric conditions. In striking contrast to developmental problems related to reelin cutbacks, improved reelin is observed in trisomy 21 subjects as well as in cognitively normal people that nevertheless had AD pathology at post mortem. However, in transgenic mouse models of AD, paid off result to reelin levels in accelerated Bortezomib ic50 AD pathology. These findings suggest that in people without developmental psychiatric disorders including SZ and BD, as myelin repair needs increase because of age-related and/or genetic degenerative processes, homeostatic up-regulation of reelin does occur that may hinder GSK3 and thus promote compensatory remyelination/repair. This compensatory up regulation of reelin seems to be deficient/absent in developmental psychiatric issues perhaps through epigenetic mechanisms and might help explain the requirement for exogenous GSK3 inhibition that seems to be given by numerous current therapeutic interventions. Lithium, a component as a salt for the therapy of BD used, can be a strong inhibitor of GSK3B. Lithium can prevent GSK3B straight via competition with magnesium and indirectly by increasing inhibitory serine phosphorylation of GSK3 through Akt. Together, these GSK3 inhibitory mechanisms likely mediate the behavioral effects of lithium and it’s therefore possible that myelination is involved in its mechanism of action. This proposition is indirectly supported by reports that that bipolar susceptibility genes are associated with white matter volume deficits that could be mitigated by reduced Akt activity in addition to treatment with lithium and increased GSK3B activity within the mind of depressed subjects at post-mortem.