Serotonin: a regulator of neuronal morphology and circuitry

Abstract

Serotonin is an important neuromodulator associated with a wide range of physiological effects in the central nervous system. The exact mechanisms whereby serotonin influences brain development are not well understood, although studies in invertebrate and vertebrate model organisms are beginning to unravel a regulatory role for serotonin in neuronal morphology and circuit formation. Recent data suggest a developmental window during which altered serotonin levels permanently influence neuronal circuitry, however, the temporal constraints and molecular mechanisms responsible are still under investigation. Growing evidence suggests that alterations in early serotonin signaling contribute to a number of neurodevelopmental and neuropsychiatric disorders. Thus, understanding how altered serotonin signaling affects neuronal morphology and plasticity, and ultimately animal physiology and pathophysiology, will be of great significance.

Figure 1

Molecular machinery of a simplified mammalian serotonin release site. Serotonin is synthesized from the amino acid tryptophan in two enzymatic steps. Hydroxylation of tryptophan by the neuronal form of tryptophan hydroxylase (TPH-2) is rate-limiting. 5-hydroxytryptophan (5-HTP) is converted to 5-hydroxytryptamine (5-HT, serotonin) by dopa-decarboxylase (DDC). After 5-HT synthesis, the vesicular monoamine transporter (VMAT) transports 5-HT into vesicles for storage. Upon vesicle fusion with the plasma membrane, 5-HT is released where it may interact with autoreceptors located on the releasing cell or heteroreceptors, serotonin receptors located on other cell types.. The serotonin transporter (SERT) transports 5-HT back into the releasing cell where it may be repackaged for release by VMAT or degraded by monoamine oxidase A (MAO-A) located on the outer mitochondrial membrane.

Figure 2