Lack of serotonin reuptake during brain development alters rostral raphe-prefrontal network formation

Abstract

Besides its “classical” neurotransmitter function, serotonin (5-HT) has been found to also act as a neurodevelopmental signal. During development, the 5-HT projection system, besides an external placental source, represents one of the earliest neurotransmitter systems to innervate the brain. One of the targets of the 5-HT projection system, originating in the brainstem raphe nuclei, is the medial prefrontal cortex (mPFC), an area involved in higher cognitive functions and important in the etiology of many neurodevelopmental disorders. Little is known, however, about the exact role of 5-HT and its signaling molecules in the formation of the raphe-prefrontal network. Using explant essays, we here studied the role of the 5-HT transporter (5-HTT), an important modulator of the 5-HT signal, in rostral raphe-prefrontal network formation. We found that the chemotrophic nature of the interaction between the origin (rostral raphe cluster) and a target (mPFC) of the 5-HT projection system was affected in rats lacking the 5-HTT (5-HTT−/−). While 5-HTT deficiency did not affect the dorsal raphe 5-HT-positive outgrowing neurites, the median raphe 5-HT neurites switched from a strong repulsive to an attractive interaction when co-cultured with the mPFC. Furthermore, the fasciculation of the mPFC outgrowing neurites was dependent on the amount of 5-HTT. In the mPFC of 5-HTT−/− pups, we observed clear differences in 5-HT innervation and the identity of a class of projection neurons of the mPFC. In the absence of the 5-HTT, the 5-HT innervation in all subareas of the early postnatal mPFC increased dramatically and the number of Satb2-positive callosal projection neurons was decreased. Together, these results suggest a 5-HTT dependency during early development of these brain areas and in the formation of the raphe-prefrontal network. The tremendous complexity of the 5-HT projection system and its role in several neurodevelopmental disorders highlights the need for further research in this largely unexplored area.

A Novel Method for Inducing Nerve Growth via Modulation of Host Resting Potential: Gap Junction-Mediated and Serotonergic Signaling Mechanisms

“…In addition, 5-HT signaling has been shown to affect the patterning of both the developing visual system and the isothalamus [ 107 , 108 ]; as in our results, these studies also implicated the 5-HT 1 family as key signaling cascade member. This is supported by several recent studies showing that serotonergic signaling modulates neural guidance directly [ 107 , 109 , 110 ]. Here we show that extracellular 5-HT availability can drive hyperinnervation and present data that implicate membrane potential as an upstream regulator of 5-HT availability developing nervous system.…”

Neurological and neuropsychological effects of low and moderate prenatal alcohol exposure

“…It is expected that prenatal 5-HTT and MAOA activities more closely reflect the activity of those polymorphisms in vitro, and could therefore be of importance for prenatal serotonin levels and neurodevelopmental effects. [111][112][113][114][115][116] Carrying the short variants of the 5-HTTLPR and MAOA-uVNTR polymorphisms is likely to result in high levels of prenatal serotonin, which, due to an inhibitory effect on nerve cell growth, [117][118][119][120][121] should result in smaller, or weaker, circuits regulated by prenatal serotonin levels. 114,122 This is likely to imply, although probably in a sexdependent manner, a greater risk of vulnerability for depression, [123][124][125][126] and alcoholism, 127,128 as well as for impulsiveness and aggressiveness.…”

Understanding autism and other neurodevelopmental disorders through experimental translational neurobehavioral models

“…Likewise, excessive serotonin levels in SERT knockout rats is associated with disrupted topographic patterning of both the barrel and visual cortex (Cases et al, 1996;Miceli et al, 2013;Murphy and Lesch, 2008;Persico et al, 2001). In addition, the outgrowth of raphe neurons to the prefrontal cortex and cortical layering are altered in SERT knockout rodents (Altamura et al, 2007;Witteveen et al, 2013). Behaviorally, SERT knockout is consistently associated with anxiety-like behavior (Kalueff et al, 2010) and impaired social interactions (Kiser et al, 2012), symptoms that are key to NDDs.…”