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

被引:38
作者
Witteveen, Josefine S. [1 ]
Middelman, Anthonieke [2 ]
van Hulten, Josephus A. [1 ]
Martens, Gerard J. M. [1 ]
Homberg, Judith R. [2 ]
Kolk, Sharon M. [1 ]
机构
[1] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Dept Mol Anim Physiol, NL-6525 GA Nijmegen, Netherlands
[2] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Med Ctr, Dept Cognit Neurosci, NL-6525 GA Nijmegen, Netherlands
关键词
explant assays; prefrontal cortex; serotonin transporter; microdissection; axon guidance; depression; SERT; autism; DEVELOPING RAT-BRAIN; KNOCK-OUT MICE; CEREBRAL-CORTEX; TRANSIENT EXPRESSION; CORTICAL DEVELOPMENT; AXON GUIDANCE; SSRI ANTIDEPRESSANTS; NEUROTROPHIC FACTOR; PRENATAL EXPOSURE; GENETIC-VARIATION;
D O I
10.3389/fncel.2013.00143
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
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页数:16
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