Environmental factors that alter serotonergic modulation during development or variation in genes involved in 5-HT signaling can cause disorders associated with defective innervation, circuit formation, and network connectivity. Numerous investigations of 5-HT’s participation in neocortical development and plasticity focused on the rodent visual and particularly the somatosensory cortex (SSC), due to its one-to-one correspondence 5-Fluoracil between the sensory system and its cortical projection area (Figure 3).

Here, to provide an example of how the serotonergic system can impact cortical development, we consider the formation of the SSC and its activity-dependent plasticity. The pronounced growth of

the cortex during development coincides with progressive serotonergic innervation. During this period, incoming 5-HT neuron terminals begin to establish synaptic interactions with target neurons and to elaborate a profuse branching pattern, matching the transient barrel-like expression and distribution of 5-HT, 5-HT1B, and 5-HT2A receptors as well as the 5-HTT, which regulates extracellular 5-HT levels by mediating high-affinity reuptake, in early-postnatal primary SSC (Mansour-Robaey et al., 1998). The barrel-like 5-HT pattern in layer 4 of the SSC stems from 5-HT uptake and vesicular storage Navitoclax in thalamocortical neurons, transiently expressing both 5-HTT and the vesicular monoamine transporter-2 (VMAT2) despite their ultimate glutamatergic specification. 5-HT dysregulation profoundly disturbs

formation of the SSC with altered cytoarchitecture of cortical layer 4, the layer that contains synapses between thalamocortical terminals and their postsynaptic target neurons (Persico et al., 2001). 5-Htt knockout mice display a lack of characteristic barrel-like clustering of layer 4 neurons in the SSC, despite relatively preserved trigeminal and thalamic patterns (other phenotypes of 5-Htt-deficient mice are described in Figure 4). 5-HT synthesis most inhibition within a narrow early postnatal time window (P0–P4) completely rescues formation of SSC barrel fields, indicating that excessive concentrations of extracellular 5-HT are deleterious to SSC development. Thus, by maintaining extracellular 5-HT concentrations below a critical threshold, transient 5-HTT expression and its permissive action in thalamocortical neurons is required for normal barrel pattern formation in neonatal rodents. Converging lines of evidence support 5-HTB receptors as direct targets of excess 5-HT.