28 Alterations in the AZD5363 migration and integration of GABAergic interneurons in cortical circuits have emerged as key processes involved in the susceptibility to psychiatric disorders.29,30 In addition to genetic alterations, early-life stress affects the migration of cortical interneurons.31 Recent work using time-lapse imaging of cortical slices has revealed that excess serotonin decreases the migration speed of cortical interneurons as well as the velocity of the pyramidal neuron in the superficial layer.32,33 Furthermore, the

distribution Inhibitors,research,lifescience,medical of both cortical interneurons and projection neurons was altered in the somatosensory cortex of neonatal SERT KO mice.32,33 Alterations in neuronal migration due to a developmental excess of serotonin could contribute to the subtle changes in the thickness of cortical layers observed in different cortical regions of SERT KO mice.34 In vitro studies combined with pharmacological approaches using time-lapse imaging revealed that serotonin receptor 6 (5-HT6R) Inhibitors,research,lifescience,medical is involved in regulating cortical neuronal migration.32,33 Interestingly, proteomic approaches indicate that 5-HT6R forms a complex with a set of proteins involved in regulating developmental processes such as the mTOR pathway,35 and 5-HT6R-mediated mTOR Inhibitors,research,lifescience,medical signaling is affected in the medial frontal cortex of mice exposed to postweaning social isolation,

a developmental model that induces schizophrenia-like phenotypes.35 The mTOR pathway has been shown to be an important signaling hub involved in autism spectrum disorders.36 Following their migration to specific cortical layers, pyramidal neurons progressively Inhibitors,research,lifescience,medical develop a dendritic arborization and receive synaptic inputs. Morphological

investigation of pyramidal neurons in the ventromedial infralimbic prefrontal cortex of SERT KO mice has revealed conflicting results with either decreased37 or increased38 apical dendritic morphologies in SERT KO mice. More studies are clearly necessary to understand these dendritic Inhibitors,research,lifescience,medical structural changes, which have been shown to be very sensitive to stress.39 Dendritic growth of cortical neurons has been shown to be regulated by serotonin fibers, creating synapses on CR cells.40 Genetically deleting the 5-HT3A receptor increases unless apical dendritic arborization of upper layer pyramidal neurons in the somatosensory cortex, whereas pharmacologically blocking SERT during pregnancy decreases their dendritic complexity.40,41 In CR neurons lacking 5-HT3A, serotonin is unable to stimulate the secretion of reelin, a glycoprotein that helps regulate neuronal migration and inhibits the growth of apical dendrites. Therefore, a reduction in reelin secretion has been proposed to lead to an abnormal hypercomplexity of apical dendrites.