Several mouse models of central serotonin depletion have been investigated. Surprisingly, no major alterations in cortical development were observed, although behavioral alterations such
as increased aggression were reported,42-46 ie, TCA segregation in the mouse barrel cortex was normal in serotonin-depleted mouse models.45 Serotonin depletion after tryptophan hydroxylase Inhibitors,research,lifescience,medical 2 (TPH2) deletion does not affect the specification of serotonin raphe neurons,46 although abnormal growth of serotonin raphe neurons in specific brain regions such as the hippocampus and nucleus accumbens were reported.47 Therefore, it is possible that subtle developmental abnormalities remain to be discovered in serotonin-depleted Inhibitors,research,lifescience,medical mouse models (ie, decreases in the density of GABAergic cortical interneuron populations have been observed in TPH2 KO mice).48 Finally, it should also be noted that during
the early stages of embryonic cortical development a lack of central serotonin production by raphe neurons could be partially compensated for by the placenta. Impact of early-life serotonin dysregulation on psychiatric-relevant phenotypes Rodent studies A large number of studies in rodents have investigated the behavioral consequences of blocking early-life SERT during specific developmental periods by administering SSRIs. Pharmacological Inhibitors,research,lifescience,medical blocking of SERT during the prenatal period41,49 or the early postnatal period49-51 has been shown to induce long-term anxiety-like and depressive-like phenotypes. Long-term stress-related behavioral effects of early-life Inhibitors,research,lifescience,medical antidepressant exposure were specific for SSRIs because antidepressants specifically blocking the norepinephrine transporter did not induce similar anxiety-like behaviors.52 SERT KO mice53 and rats54 exhibited similar types of stress-related behavioral phenotypes including increased hypothalamo-pituitary-adrenal (HPA) reactivity to stressors Inhibitors,research,lifescience,medical and impaired fear extinction.38,55,56 Blocking the 5-HT1A receptor during the early postnatal
period57 reversed the depression-like phenotypes and sleep disturbances observed in SERT KO mice, suggesting an important role for this receptor in mediating the developmental effects of serotonin. In addition to these findings, conditional deletion of the 5-HT1A receptor from during development but not during adulthood induces anxiety-like behaviors. The contribution of 5-HT1A presynaptic autoreceptors located on serotonin raphe neurons versus postsynaptic heteroreceptors remains to be fully Selleck Selumetinib established in these models.58 In addition to anxiety-like and depressive-like phenotypes, autism-related behavioral dimensions (eg, reduced social interactions, increased self-grooming, and impaired sensory-motor integration) have also been reported in genetic and pharmacological rodent models of early-life SERT blockade.