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Embracing diversity in the 5-HT neuronal system

Abstract

Neurons that synthesize and release 5-hydroxytryptamine (5-HT; serotonin) express a core set of genes that establish and maintain this neurotransmitter phenotype and distinguish these neurons from other brain cells. Beyond a shared 5-HTergic phenotype, these neurons display divergent cellular properties in relation to anatomy, morphology, hodology, electrophysiology and gene expression, including differential expression of molecules supporting co-transmission of additional neurotransmitters. This diversity suggests that functionally heterogeneous subtypes of 5-HT neurons exist, but linking subsets of these neurons to particular functions has been technically challenging. We discuss recent data from molecular genetic, genomic and functional methods that, when coupled with classical findings, yield a reframing of the 5-HT neuronal system as a conglomeration of diverse subsystems with potential to inspire novel, more targeted therapies for clinically distinct 5-HT-related disorders.

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Acknowledgements

The authors are grateful to the peer reviewers for their thoughtful input and to members of the Dymecki laboratory for discussions related to this article. The work of the authors is supported by US National Institutes of Health grants (P01 HD036379 to B.W.O., K.G.C. and S.M.D.; R01 DA034022 to B.W.O. and S.M.D.; R21 DA036056 to S.M.D.; and R01 DA 021801 to K.G.C.), the Blavatnik Biomedical Accelerator (grant to B.W.O. and S.M.D.) and the GVR Khodadad Family Foundation (grant to S.M.D.).

Reviewer information

Nature Reviews Neuroscience thanks P. Gaspar, C. Lowry and T. Sharp for their contribution to the peer review of this work.

Author information

The authors all researched data for the article, provided substantial contributions to discussion of content, wrote the article and reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Correspondence to Benjamin W. Okaty or Susan M. Dymecki.

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Glossary

Rhombomeres

Transiently appearing segmented divisions of the developing embryonic hindbrain of vertebrates that are distinguishable morphologically. Rhombomeres function as molecularly discrete, transverse progenitor domains, each giving rise to cell populations with some restriction in fates.

Isthmus

The most rostral transverse segment of the developing embryonic hindbrain. It abuts the midbrain at its rostral border and rhombomere 1 at its caudal border and thus is often referred to as the midbrain–hindbrain junction. The isthmus gives rise to select neurons.

Fate mapping

Indelibly marking a regionally or temporally restricted cohort of cells so as to be able to link labelled mature cells to their developmental origin. Genetic fate mapping involves the use of gene-enhancer-driven Cre or Flp recombinase expression to ‘capture’ cells for constitutive reporter expression. Reporter expression results from Cre-mediated or Flp-mediated recombination of an otherwise ‘silent’ transgene.

Intersectional genetics

Here refers specifically to the use of gene-enhancer-driven Cre and Flp recombinase expression in conjunction with expression of a dual-recombinase-responsive reporter or effector transgene to afford precise labelling or manipulation of cells defined by a history of both Cre and Flp expression.

Transcriptomic technologies

High-throughput approaches, such as microarray gene chip and next-generation RNA sequencing, that allow measurement of the relative abundances of all transcripts (including mRNAs, non-coding RNAs and microRNAs) expressed by a tissue, a pool of cells or a single cell or contained in an isolated cellular compartment, such as the nucleus or synaptosome.

Co-transmission

Release of more than one neurotransmitter from a single neuron, either from the same or segregated release sites.

Optogenetics

The use of photoactivable ion channel proteins cloned from algae to acutely excite or inhibit transfected cells using light.

Intrinsic electrical properties

The set of electrical characteristics a neuron possesses by virtue of its membrane permeability and capacitance, morphology and its intracellular ionic content and the ionic driving forces acting upon on it. Typically, intrinsic properties are divided into passive and active properties.

Fibre photometry

The use of a brain-implanted optical fibre to visualize and record local Ca2+ fluctuations, a proxy for neuroelectrical activity, as revealed by a genetically encoded calcium indicator, such as GCaMP6. Typically, this method does not provide single-neuron activity resolution but reflects aggregate Ca2+ fluxes coming from populations of cells.

Volume transmission

Neuronal release of neurotransmitter in a diffuse manner, either in the absence of a closely apposed postsynaptic site or in the absence of an efficient local reuptake mechanism, such that cells and synapses distal to the locus of release may ultimately bind the released transmitter.

Selective serotonin reuptake inhibitors

(SSRIs). SSRIs are a class of pharmacological compounds that block the reuptake of extracellular 5-HT by the serotonin transporter, frequently prescribed to treat major depressive disorder and increasingly prescribed to treat other affective disorders such as anxiety and obsessive–compulsive disorder.

Prepulse inhibition

(PPI). The tendency for an organism to display an attenuated response to a given sensory stimulus if it is preceded by a (typically weaker) prestimulus; for example, as observed in the blunting of the acoustic startle reflex to a sudden unexpected loud noise by a preceding quieter tone.

DREADD

An acronym that stands for designer receptors exclusively activated by designer drugs, an approach that deploys metabotropic receptors that have been re-engineered to respond preferentially to designer compounds (which are otherwise biologically inert) in order to manipulate the activity of transfected cells.

Clozapine N-oxide

An engineered ligand, derived from the antipsychotic psychoactive drug clozapine, that activates DREADD (designer receptors exclusively activated by designer drugs) receptors but is otherwise inert (in its unmetabolized form).

Chemogenetics

The use of DREADD (designer receptors exclusively activated by designer drugs) technology to acutely manipulate the activity of a population of cells, typically to investigate its in vivo functions.

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Fig. 1: Overview of 5-HT neuron diversity.
Fig. 2: Sagittal cross-sectional representation of the mature mouse brainstem with labelled raphe subdomains and corresponding genetically fate-mapped cohorts of Pet1 neurons.
Fig. 3: 5-HT synthesis pathway and core 5-HT neuron molecular phenotype.
Fig. 4: Constellations of differentially expressed genes distinguish Pet1 neuron subtypes defined by lineage and anatomy.
Fig. 5: Summary of Drd2–Pet1 neuron phenotype, integrating across domains.
Fig. 6: An ‘epigenetic landscape’ model of hypothesized 5-HT neuron subtypes.