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Raphe serotonin neurons are not homogenous: Electrophysiological, morphological and neurochemical evidence
Open accessAbstract
The median (MR) and dorsal raphe (DR) nuclei contain the majority of the 5-hydroxytryptamine (5-HT, serotonin) neurons that project to limbic forebrain regions, are important in regulating homeostatic functions and are implicated in the etiology and treatment of mood disorders and schizophrenia. The primary synaptic inputs within and to the raphe are glutamatergic and GABAergic. The DR is divided into three subfields, i.e., ventromedial (vmDR), lateral wings (lwDR) and dorsomedial (dmDR). Our previous work shows that cell characteristics of 5-HT neurons and the magnitude of the 5-HT(1A) and 5-HT(1B) receptor-mediated responses in the vmDR and MR are not the same. We extend these observations to examine the electrophysiological properties across all four raphe subfields in both 5-HT and non-5-HT neurons. The neurochemical topography of glutamatergic and GABAergic cell bodies and nerve terminals were identified using immunohistochemistry and the morphology of the 5-HT neurons was measured. Although 5-HT neurons possessed similar physiological properties, important differences existed between subfields. Non-5-HT neurons were indistinguishable from 5-HT neurons. GABA neurons were distributed throughout the raphe, usually in areas devoid of 5-HT neurons. Although GABAergic synaptic innervation was dense throughout the raphe (immunohistochemical analysis of the GABA transporters GAT1 and GAT3), their distributions differed. Glutamate neurons, as defined by vGlut3 anti-bodies, were intermixed and co-localized with 5-HT neurons within all raphe subfields. Finally, the dendritic arbor of the 5-HT neurons was distinct between subfields. Previous studies regard 5-HT neurons as a homogenous population. Our data support a model of the raphe as an area composed of functionally distinct subpopulations of 5-HT and non-5-HT neurons, in part delineated by subfield. Understanding the interaction of the cell properties of the neurons in concert with their morphology, local distribution of GABA and glutamate neurons and their synaptic input, reveals a more complicated and heterogeneous raphe. These results provide an important foundation for understanding how specific subfields modulate behavior and for defining which aspects of the circuitry are altered during the etiology of psychological disorders.
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“Accumulating evidence points to physiological and molecular heterogeneity within the DR serotonin system (Calizo et al., 2011; Cohen et al., 2015; Fernandez et al., 2016; Okaty et al., 2015).”
From Anatomically defined and functionally distinct dorsal raphe serotonin sub-systems (2018) · cites this paper as Calizo et al., 2011
In the citing paper
“Evidence has suggested that the DR and MR serotonin systems differ in developmental origin, connectivity, physiology, and behavioral function (Alonso et al., 2013; Calizo et al., 2011; Okaty et al., 2019).”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Calizo et al., 2011
In the citing paper
“Slice physiology recording showed that the serotonin neurons in the MR and DR have different electrophysiological characteristics, such as resting potential, membrane resistance, and reaction to serotonin receptor-1A agonist (Calizo et al., 2011; Fernandez et al., 2016).”
From Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei (2019) · cites this paper as Calizo et al., 2011
In the citing paper
“Even bona fide DRN 5-HT neurons are molecularly, anatomically, and physiologically heterogeneous.”
From Molecular and anatomical organization of the dorsal raphe nucleus (2019) · cites this paper as Calizo et al., 2011
In the citing paper
“Although DRN 5-HT neurons share a common developmental lineage (Deneris and Gaspar, 2018; Jensen et al., 2008), DRN 5-HT neurons in different subregions express different G protein-coupled receptors and vesicular transporters, suggesting spatial clustering of functionally specialized neurons (Calizo et al., 2011; Fernandez et al., 2016; Lowry et al., 2000; Templin et al., 2012).”
From Molecular and anatomical organization of the dorsal raphe nucleus (2019) · cites this paper as Calizo et al., 2011
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Metadata
- Authors
- Calizo, L. H., Akanwa, A., Ma, X., Pan, Y.-Z., Lemos, J. C., Craige, C., Heemstra, L. A., & Beck, S. G.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Beck, Sheryl G.
- ORCID
- Lemos, Julia C.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 61
- Issue
- 3
- Pages
- 524-543
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC3120045
- OpenAlex
- W1987083929
- Cited by
- 252
- References
- 121
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 14 · 2023: 18 · 2022: 9 · 2021: 17 · 2020: 22 · 2019: 25 · 2018: 16 · 2017: 17 · 2016: 16 · 2015: 23 · 2014: 16 · 2013: 25 · 2012: 14
- FWCI
- 7.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (MH0754047)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Keywords
- raphe nuclei, serotonergic neurons, dorsal raphe nucleus, median raphe, neuronal heterogeneity, GABAergic neurons, glutamatergic neurons, VGLUT3, GABA transporters, dendritic morphology, synaptic input, 5-HT1A receptor, 5-HT1B receptor, mood disorders, schizophrenia
- MeSH terms
- Animals, Brain Chemistry, Dendrites, Glutamate Decarboxylase, Immunohistochemistry, Male, Membrane Potentials, Synaptic Transmission, Neurons, Raphe Nuclei, Tryptophan Hydroxylase, Electric Impedance, Rats, Sprague-Dawley, Patch-Clamp Techniques, Receptor, Serotonin, 5-HT1A, Receptor, Serotonin, 5-HT1B, GABA Plasma Membrane Transport Proteins, Glucose Transporter Type 3, Rats
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