Insights into the complex influence of 5-HT signaling on thalamocortical axonal system development

Abstract

The topographic organization of the thalamocortical axons (TCAs) in the barrel field (BF) in the rodent primary somatosensory cortex results from a succession of temporally and spatially precise developmental events. Prenatally, growth and guidance mechanisms enable TCAs to navigate through the forebrain and reach the cortex. Postnatally, TCAs grow into the cortex, and the refinement of their terminal arborization pattern in layer IV creates barrel-like structures. The combined results of studies performed over the past 20 years clearly show that serotonin (5-hydroxytryptamine; 5-HT) signaling modulates these pre- and early postnatal developmental processes. In this context, 5-HT signaling can purposely be described as 'modulating' rather than 'controlling' because developmental alterations of 5-HT synthesis, uptake or degradation either have a dramatic, moderate or no effect at all on TCA pathway and BF formation. In this review we summarize and compare the outcomes of diverse pharmacological and genetic manipulations of 5-HT signaling on TCA pathway and BF formation, in an attempt to understand these discrepancies.

Figure 1

Decreased extracellular brain serotonin (5-HT) does not affect cortical barrel field (BF) formation. Despite the profound reduction of brain 5-HT in VMAT2-cKO mice (see text), the BF appears grossly normal at P5 (B), similar to wild type (A). (C), similarly in the Pet1-KO mice where brain 5-HT concentration is reduced by ~70%, BF pattern appears normal at P7. BF formation was visualized in flattened cortex preparations stained with a 5-HTT (SERT) antibody.

Figure 2

Timeline of the genetic and pharmacological alterations of 5-HT signaling and their effects on thalamocortical axons (TCA) pathway and cortical barrel field (BF) formation. Manipulations leading to increased 5-HT signaling during development are illustrated in the top panel. Overexpression of 5-HT1B/1D receptors (IUE: in utero electroporation) alters TCA pathway prenatally; the effect on postnatal BF formation is unknown (dotted box). In the SERT-KO and MAOA-KO mice, extracellular brain 5-HT concentration is increased and BF formation is altered postnatally. The blue arrows represent the duration of the effect on 5-HT signaling. The bottom panel illustrates manipulations leading to a decrease of 5-HT signaling prenatally (IUE) and/or pre- and postnatally (knockout mice and p-chlorophenylalanine (PCPA) treatment). Knocking down 5-HT1B/1D receptors expression by in utero electroporation alters TCA pathway prenatally, with unknown effect on postnatal BF formation. In most of the genetic mouse models, prenatal effects on TCA pathway formation were not analyzed in detail. The potential prenatal effects on the placental source of 5-HT, inferred from the targeted genes being expressed in the placenta, are indicated (yellow line).

Figure 3

Potential mechanism by which increased extracellular serotonin (5-HT) in the MAOA-KO mice affects cortical barrel field (BF) formation. (A), in wild type (C3H; C3H/HeJ background) mice 5-HT signals simultaneously through both 5-HT1B and 5-HT1D receptors, which are transiently expressed by thalamic neurons and present on axon terminals (see text). (B), increased extracellular 5-HT concentration in the MAOA-KO mice leads to over-activation of 5-HT1B and 5-HT1D receptors, and to an absence of clear BF formation as observed at P7 in flattened cortex preparations stained with a 5-HT antibody. (C), in the absence of 5-HT1B receptors (MAOA/5-HT1B –Double KO), the MAOA-KO phenotype is rescued, suggesting that residual 5-HT signaling is sufficient for normal BF formation, despite the increased extracellular 5-HT concentration. Since BF patterning is not altered in 5-HT1B-KO mice (see text), the model proposes that 5-HT1D receptors may provide sufficient signaling for normal BF formation in the absence of 5-HT1B receptors, with or without elevated extracellular 5-HT concentration. BF formation (right panels) was visualized in flattened cortex preparations stained with CO histochemistry.