A Subpopulation of Serotonergic Neurons That Do Not Express the 5-HT1A Autoreceptor

Abstract

5-HT neurons are topographically organized in the hindbrain, and have been implicated in the etiology and treatment of psychiatric diseases such as depression and anxiety. Early studies suggested that the raphe 5-HT neurons were a homogeneous population showing similar electrical properties, and feedback inhibition mediated by 5-HT1A autoreceptors. We utilized histochemistry techniques in ePet1-eGFP and 5-HT1A-iCre/ R26R mice to show that a subpopulation of 5-HT neurons do not express the somatodendritic 5-HT1A autoreceptor mRNA. In addition, we performed patch-clamp recordings followed by singlecell PCR in ePet1-eGFP mice. From 134 recorded 5-HT neurons located in the dorsal, lateral, and median raphe, we found lack of 5-HT1A mRNA expression in 22 cells, evenly distributed across raphe subfields. We compared the cellular characteristics of these neuronal types and found no difference in passive membrane properties and general excitability. However, when injected with large depolarizing current, 5-HT1A-negative neurons fired more action potentials, suggesting a lack of autoinhibitory action of local 5-HT release. Our results support the hypothesis that the 5-HT system is composed of subpopulations of serotonergic neurons with different capacity for adaptation.T he 5-hydroxytryptamine (5-HT, serotonin) neurotransmitter system has been strongly implicated in the etiology and treatment of psychiatric diseases such as depression and anxiety. 1,2 5-HT neurons are topographically organized in the hindbrain where distinct groups of neurons receive and send synaptic inputs from/to specific brain regions, suggesting that the neuronal activity of subpopulation of 5-HT neurons is under discrete spatiotemporal control. 3 Given the occurrence of neurochemically diverse neurons in the raphe nuclei, early studies proposed a series of features or "landmarks", common to all 5-HT neurons, that would help in the identification of putative 5-HT cells. 4−6 These included the regular firing of broad action potentials (clocklike activity) followed by a large afterhyperpolarization potential, high input resistance, and suppression of firing by 5-hydroxytryptamine receptor 1A (5-HT1A) agonists. 4−6 However, this dogma is progressively being questioned. Recent studies found that the electrophysiological characteristics of chemically identified 5-HT neurons in the raphe are more diverse than originally thought. Using juxtacellular labeling techniques, it was found that, besides the population of slow-firing clocklike cells, in vivo discharge of 5-HT neurons also includes subpopulations of fastfiring and bursting neurons. 7,8 Moreover, in vitro patch-clamp studies conducted in brain slices demonstrated a high degree of variability in the passive and active membrane properties of 5-HT neurons. 9,10 Finally, anatomical and electrophysiological studies showed that 5-HT1A receptors are not only expressed in 5-HT neurons, but also in other neuronal classes in the raphe nuclei. 10−12 Together these evidence call to re-evaluate the defi...

Neuronal Phenotype Dependency of Agonist-Induced Internalization of the 5-HT1ASerotonin Receptor

“…Furthermore, after such a sustained treatment, the full agonists were able to induce receptor endocytosis (up to 400%) in only a subpopulation of hippocampal (HIGH) neurons, thereby reflecting the existence of a heterogeneous population of neurons in hippocampal cultures. Whereas 5-HT 1A R is expressed almost exclusively in serotonergic neurons in the raphe area in rats (Yasufuku-Takano et al, 2008;Kiyasova et al, 2013), only pyramidal neurons (mainly in CA1 subarea) are expressing endogenously 5-HT 1A R in the hippocampus (Riad et al, 2001). Differences between hippocampal neurons that exhibit (HIGH) or not (LOW) 5-HT-or 5-CT-induced BBS-5-HT 1A R internalization probably relied on their respective phenotypic characteristics (endogenous expression of the 5-HT 1A R, different coupling pathways, or expression of specific proteins) that remain to be identified.…”

Gata2 and Gata3 regulate the differentiation of serotonergic and glutamatergic neuron subtypes of the dorsal raphe

“…Transcriptome analyses have mapped the differences in gene expression between and within the rostral and caudal clusters (Wylie et al, 2010;Okaty et al, 2015). In addition, the dorsal and median raphe serotonergic neurons display heterogeneity in their serotonin autoreceptor (Htr1a) and serotonin transporter (Sert; also known as Slc6a4) expression, electrophysiological properties, axonal morphology and susceptibility to neurotoxins (Mamounas et al, 1991;Crawford et al, 2010;Calizo et al, 2011;Kiyasova et al, 2013). Serotonergic neurons in the dorsal raphe are also thought to differ in their use of co-neurotransmitters (Fu et al, 2010).…”

5-HT1B autoreceptors differentially modulate the expression of conditioned fear in a circuit-specific manner

“…As shown in Figure 5c, transgene expression is detected in both Tph-positive and Tph-negative cells. Recent evidence suggests that subdivisions in the DRN amongst serotonergic neurons themselves may have distinct functional roles in behavior, not only in their somatotopic organization (Paul and Lowry, 2013), but also in their expression of various genes that had previously been thought to define whether a cell was serotonergic, such as 5-HT 1A autoreceptors (Gaspar and Lillesaar, 2012, Kiyasova et al, 2013). A greater understanding of the organization of the DRN is necessary, as well as an investigation into the anatomical connections between subdivisions of the DRN and the different amygdaloid nuclei.…”