Lack of serotonin reuptake during brain development alters rostral raphe-prefrontal network formation
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 represents one of the earliest neurotransmitter systems to innervate the brain. One of the targets of the 5-HT projection syst...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2013-10-01
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| Series: | Frontiers in Cellular Neuroscience |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fncel.2013.00143/full |
| _version_ | 1819128785632493568 |
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| author | Josefine Storm Witteveen Anthonieke eMiddelman Josephus Adrianus van Hulten Gerardus Julianus Maria Martens Judith Regina Homberg Sharon Margriet Kolk |
| author_facet | Josefine Storm Witteveen Anthonieke eMiddelman Josephus Adrianus van Hulten Gerardus Julianus Maria Martens Judith Regina Homberg Sharon Margriet Kolk |
| author_sort | Josefine Storm Witteveen |
| collection | DOAJ |
| description | 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 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. |
| first_indexed | 2024-12-22T08:33:21Z |
| format | Article |
| id | doaj.art-97a7085c33394f10b21658044de3bcc9 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-22T08:33:21Z |
| publishDate | 2013-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-97a7085c33394f10b21658044de3bcc92022-12-21T18:32:26ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022013-10-01710.3389/fncel.2013.0014349926Lack of serotonin reuptake during brain development alters rostral raphe-prefrontal network formationJosefine Storm Witteveen0Anthonieke eMiddelman1Josephus Adrianus van Hulten2Gerardus Julianus Maria Martens3Judith Regina Homberg4Sharon Margriet Kolk5Radboud UniversityDonders Institute for Brain, Cognition and BehaviorRadboud UniversityRadboud UniversityDonders Institute for Brain, Cognition and BehaviorRadboud UniversityBesides its ‘classical’ neurotransmitter function, serotonin (5-HT) has been found to also act as a neurodevelopmental signal. During development, the 5-HT projection system 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.http://journal.frontiersin.org/Journal/10.3389/fncel.2013.00143/fullDepressionMicrodissectionPrefrontal Cortexautismaxon guidanceserotonin transporter |
| spellingShingle | Josefine Storm Witteveen Anthonieke eMiddelman Josephus Adrianus van Hulten Gerardus Julianus Maria Martens Judith Regina Homberg Sharon Margriet Kolk Lack of serotonin reuptake during brain development alters rostral raphe-prefrontal network formation Frontiers in Cellular Neuroscience Depression Microdissection Prefrontal Cortex autism axon guidance serotonin transporter |
| title | Lack of serotonin reuptake during brain development alters rostral raphe-prefrontal network formation |
| title_full | Lack of serotonin reuptake during brain development alters rostral raphe-prefrontal network formation |
| title_fullStr | Lack of serotonin reuptake during brain development alters rostral raphe-prefrontal network formation |
| title_full_unstemmed | Lack of serotonin reuptake during brain development alters rostral raphe-prefrontal network formation |
| title_short | Lack of serotonin reuptake during brain development alters rostral raphe-prefrontal network formation |
| title_sort | lack of serotonin reuptake during brain development alters rostral raphe prefrontal network formation |
| topic | Depression Microdissection Prefrontal Cortex autism axon guidance serotonin transporter |
| url | http://journal.frontiersin.org/Journal/10.3389/fncel.2013.00143/full |
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