Abstract
The serotonergic system of mammals innervates virtually all the central nervous system and regulates a broad spectrum of behavioral and physiological functions. In mammals, serotonergic neurons located in the rostral raphe nuclei encompass diverse sub-systems characterized by specific circuitry and functional features. Substantial evidence suggest that functional diversity of serotonergic circuits has a molecular and connectivity basis. However, the landscape of intrinsic developmental mechanisms guiding the formation of serotonergic sub-systems is unclear. Here, we employed developmental disruption of gene expression specific to serotonergic subsets to probe the contribution of the tyrosine kinase receptor ErbB4 to serotonergic circuit formation and function. Through an in vivo loss-of-function approach, we found that ErbB4 expression occurring in a subset of serotonergic neurons, is necessary for axonal arborization of defined long-range projections to the forebrain but is dispensable for the innervation of other targets of the serotonergic system. We also found that Erbb4-deletion does not change the global excitability or the number of neurons with serotonin content in the dorsal raphe nuclei. In addition, ErbB4-deficiency in serotonergic neurons leads to specific behavioral deficits in memory processing that involve aversive or social components. Altogether, our work unveils a developmental mechanism intrinsically acting through ErbB4 in subsets of serotonergic neurons to orchestrate a precise long-range circuit and ultimately involved in the formation of emotional and social memories.
Highlights
Serotonin ( known as 5-hydroxytryptamine (5HT)) is a phylogenetically conserved signaling molecule (Hay-Schmidt, 2000) regulating diverse emotional, cognitive and neurovegetative functions
To understand whether ErbB4 is involved in serotonergic circuit development, we employed mouse genetics to label serotonergic neurons with a fluorescent protein tdTomato reporter controlled by a Cre recombinase driven by Pet1 promoter (Figure 1A), a determinant of serotonergic fate (Hendricks et al, 1999)
Having identified that ErbB4 is expressed in a subset of adult dorsal raphe nucleus (DRN) Pet1+ neurons, we examined whether ErbB4 is involved in serotonergic circuit development
Summary
Serotonin ( known as 5-hydroxytryptamine (5HT)) is a phylogenetically conserved signaling molecule (Hay-Schmidt, 2000) regulating diverse emotional, cognitive and neurovegetative functions. Serotonergic neurons distributed in the raphe nuclei of the brainstem are clustered in different groups topographically classified as B1–B9 (Dahlstrom and Fuxe, 1964). The largest group of serotonergic neurons allocate within the dorsal (B7 and B6) and median raphe (B8) nuclei (DRN and MRN, respectively) and develop exuberant axonal projections targeting almost every brain region. A functionally diverse competence of DRN and MRN serotonergic circuits is thought to result from the development of extensive axonal projections reaching multiple brain targets. DRN and MRN serotonergic circuit formation is guided by intrinsic and extrinsic factors. Additional findings suggest that cell adhesion molecules (Cadherin 13) molecules and guidance cues (Eph5/ephrinA5) are involved in the negative regulation of axon outgrowth and/or pathfinding in addition to neuron proliferation of serotonergic neurons (Forero et al, 2017; Teng et al, 2017). High levels of ephrinA5 receptor expression in DRN has been described to repel axon growth in the hypothalamus and regulate proper arborization of serotonergic fibers in the olfactory bulb through repulsion by ephrinA5 (Teng et al, 2017)
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