Serotonin: a regulator of neuronal morphology and circuitry

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.

Introduction

In addition to its physiological role, growing evidence suggests the neuromodulator serotonin (5-hydroxytryptamine, 5-HT) also regulates the connectivity of the brain by modulating developmental cellular migration and cytoarchitecture. Data obtained from multiple animal models also support the hypothesis that serotonin autoregulates serotonergic branch morphology. Therefore, the influence of serotonin on neuronal morphology is inherently complex and alterations in serotonergic modulation could have unexpected effects on brain morphology, physiology, and behavior. Serotonin levels during development can be altered by a number of factors, including nutrition [1], stress [2], infection [3], genetic polymorphisms [4], and pharmacological compounds such as selective serotonin reuptake inhibitors (SSRIs) [5] and certain drugs of abuse. Thus, disorders associated with faulty neural connectivity or innervation could be rooted in early circuit errors elicited by primary dysfunction in serotonergic physiology.

Serotonergic innervation is relatively evenly distributed throughout the CNS, indicating that most brain regions receive serotonergic modulation 6, 7. Evidence suggests serotonin is released in an even sprinkler-type fashion termed volume transmission, and functional concentrations of neurotransmitter are maintained several microns from release sites [8]. Serotonin's diverse effects are mediated by a number of receptors distributed throughout the body. To date, at least fourteen different serotonin receptor subtypes have been identified in mammals and are grouped into seven families (5-HT₁–5-HT₇) [9]. All of the serotonin receptors are G-protein-coupled receptors except the 5-HT₃ ligand-gated ion channel. Figure 1 contains a simplified cartoon of a serotonin release site. Despite the omnipresence of serotonergic innervation, invertebrate and vertebrate models lacking most central serotonergic neurons 7, 10, 11 or neuronal serotonin synthesis enzymes 12, 13, 14 are capable of developing into adulthood with grossly normal brain morphology, although some degree of perinatal mortality is observed. Of the serotonin receptor knockout animals generated thus far, only one, 5-HT_2B (Htr2b), causes embryonic lethality due to defective heart development [15]. However, an important caveat to these studies remains. With the possible exception of the tph-1 C. elegans mutant lacking the serotonin biosynthetic enzyme tryptophan hydroxylase (TPH) [13], the serotonin-null animal models generated to date fail to specifically abolish all serotonin in the CNS, even when both the central and peripheral serotonin synthesis genes are simultaneously ablated (Table 1). Furthermore, maternally-derived serotonin influences pre-neural embryonic patterning in frog embryos and craniofacial development in mice [16] and can influence early nervous system development in genetic mouse models of central serotonin depletion. The persistence of detectable serotonin and survival of animals with reduced serotonin function indicate that redundant mechanisms ensure adequate serotonin levels during early development, and adult animals appear able to adapt to significantly reduced or absent serotonin signaling. The absence of gross brain malformations in these animals suggests that the effects of serotonin on neural morphology are subtle and require analysis at the cellular level in order to be fully appreciated.