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.
Highlights
It has become increasingly clear that several “classical” neurotransmitters, such as serotonin (5-HT), act as neurodevelopmental signals to direct the assembly of the developing brain (Lauder, 1990; Whitaker-Azmitia et al, 1996; Buznikov et al, 2001; Sodhi and Sanders-Bush, 2004; Cunningham et al, 2005; Riccio et al, 2009; Souza and Tropepe, 2011; Bonnin and Levitt, 2012; Migliarini et al, 2012)
The rostral and intermediate subareas correspond to the dorsal raphe nucleus (DR) which mainly projects to the forebrain, including the medial prefrontal cortex (mPFC) (Van Bockstaele et al, 1993; Waselus et al, 2011)
The present study evaluates the trophic nature of the interaction between the origin and a target of the 5-HT projection system and how this interaction is modulated by the lack of the 5-HT transporter (5-HTT) during development
Summary
It has become increasingly clear that several “classical” neurotransmitters, such as serotonin (5-HT), act as neurodevelopmental signals to direct the assembly of the developing brain (Lauder, 1990; Whitaker-Azmitia et al, 1996; Buznikov et al, 2001; Sodhi and Sanders-Bush, 2004; Cunningham et al, 2005; Riccio et al, 2009; Souza and Tropepe, 2011; Bonnin and Levitt, 2012; Migliarini et al, 2012). SSRIs given to the pregnant mother to treat depression, will increase the extracellular 5-HT in the mother and in the brains of the unborn child (Rampono et al, 2004; Gentile and Galbally, 2011). These children acquire an increased risk to develop reduced somatosensory responses (Oberlander et al, 2009) and/or psychomotor control (Casper et al, 2011), and appear to have a higher risk to develop autism-like symptoms (Croen et al, 2011)
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