Abstract
The serotonin (5-HT) system densely innervates many brain areas and is important for proper brain development. To specifically ablate the 5-HT system we generated mutant mice carrying a floxed Munc18-1 gene and Cre recombinase driven by the 5-HT-specific serotonin reuptake transporter (SERT) promoter. The majority of mutant mice died within a few days after birth. Immunohistochemical analysis of brains of these mice showed that initially 5-HT neurons are formed and the cortex is innervated with 5-HT projections. From embryonic day 16 onwards, however, 5-HT neurons started to degenerate and at postnatal day 2 hardly any 5-HT projections were present in the cortex. The 5-HT system of mice heterozygous for the floxed Munc18-1 allele was indistinguishable from control mice. These data show that deletion of Munc18-1 in 5-HT neurons results in rapid degeneration of the 5-HT system and suggests that the 5-HT system is important for postnatal survival.
Highlights
The 5-HT system consists of clusters of cell bodies in the midbrain raphe nuclei, with the largest clusters in the median raphe nucleus and the dorsal raphe nucleus (DRN)
We crossed serotonin reuptake transporter (SERT)-Crecre/wt Munc18-1lox/wt mice with SERT-Crewt/wt Munc18-1lox/wt mice which should result in 12.5% of offspring which have SERT-Crecre/wt and Munc18-1lox/lox genotypes
Three SERT-Crecre/wt Munc18-1lox/lox mice were found, whereas based on Mendelian ratio the expected number of SERT-Crecre/wt Munc18-1lox/lox mice should be 13, giving a 77% mortality rate in SERT-Crecre/wt Munc18-1lox/lox mice (Fig. 1B). These three remaining SERT-Crecre/wt Munc181lox/lox mice all died in the fourth postnatal week
Summary
The 5-HT system consists of clusters of cell bodies in the midbrain raphe nuclei, with the largest clusters in the median raphe nucleus and the dorsal raphe nucleus (DRN). Several brain areas receive dense 5-HT innervation and 5-HT is released both synaptically and as volume transmission [1,2]. Due to this and to the several 5-HT receptor subtypes which are present in the brain, 5-HT has many roles and influences many processes in the brain [3]. Neurogenesis of 5-HT neurons in the mouse brain occurs in the ventral rhombencephalon around embryonic day (E) 10 [4]. 5-HT neurons begin to synthesize and secrete 5-HT and start growing out axons. Target areas such as the forebrain and the hippocampus are densely innervated with 5-HT projections. The maturation of the 5-HT network is completed
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