Genetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders?

doi:10.1016/S0006-3223(98)00121-8

Biological Psychiatry

Volume 44, Issue 3, 1 August 1998, Pages 179-192

https://doi.org/10.1016/S0006-3223(98)00121-8 Get rights and content

Abstract

Serotonin (5-HT) is an important regulator of morphogenetic activities during early central nervous system development, including cell proliferation, migration, and differentiation. The 5-HT transporter (5-HTT) plays a pivotal role in brain 5-HT homeostasis. It is also the initial target for both antidepressant drugs and drugs of abuse, some of which are potent neurotoxins. A polymorphism in the 5′-flanking regulatory region of the 5-HTT gene that results in allelic variation of 5-HTT expression is associated with anxiety-related personality traits and may influence the risk of developing affective disorders. Progress in 5-HTT gene inactivation studies are also changing views of the relevance of adaptive 5-HT uptake function in brain development and plasticity as well as processes underlying drug dependence and neurodegeneration. Despite evidence for a potential role of the 5-HTT in the integration of synaptic connections in the mammalian brain during development, adult life, and old age, detailed knowledge of the molecular mechanisms involved in these fine-tuning processes is just beginning to emerge. Integration of various strategies, including molecular genetic, transgenic, and gene transfer techniques, will allow elucidation of the 5-HTT’s role in brain development, plasticity, and degeneration as well as in affective illness, drug abuse, and dementia.

Introduction

Attention has recently been focused on monoaminergic neurotransmitters as potential morphogenetic factors in the developing central nervous system. The early expression of the biogenic amine serotonin (5-HT) in developing midbrain raphe neurons and their projecting terminals prior to synaptogenesis and onset of serotonergic signaling indicates that it is an important regulator of morphogenetic activities during early embryonic development, including cell proliferation, migration, and differentiation Lauder 1990, Lauder 1993. These phylogenetically ancient functions are reiterated in the developing brain, as illustrated by the roles of 5-HT in the neural development of invertebrates (Bailey et al 1992).

In the brain of adult humans, serotonergic raphe neurons diffusely project to a variety of brain regions (e.g., cortex, amygdala, hippocampus) and play known roles in integrating emotion, cognition, motor function, and pain as well as circadian and neuroendocrine functions including food intake, sleep, and sexual activity. The diversity of physiologic functions is due to the fact that 5-HT orchestrates the activity and interaction of several other neurotransmitter systems. While 5-HT acts like a master control neurotransmitter within this highly complex system of neural communication mediated by multiple pre- and postsynaptic 5-HT receptor subtypes, 5-HT transport into the presynaptic neuron by a single protein represents a functional “bottle neck.” The 5-HT transporter (5-HTT) removes 5-HT from the synaptic cleft and determines the magnitude and duration of postsynaptic receptor-mediated signaling, thus playing a pivotal role in the fine-tuning of 5-HT neurotransmission (Blakely et al 1994, Uhl and Johnson 1994, Lesch 1997, and references therein). The 5-HTT is also the initial target for several antidepressant drugs (e.g., clomipramine, fluoxetine), anorectic drugs (D-fenfluramine, “Redux”), and drugs of abuse [substituted amphetamines such as methylenedioxymethamphetamine (MDMA), “ecstasy”], some of which are potent neurotoxins.

There have been substantial advances in the elucidation of the 5-HTT gene’s organization and regulation. A polymorphism in the 5′-flanking regulatory (promoter) region of the 5-HTT gene that results in allelic variation in functional 5-HTT expression is associated with anxiety- and depression-related personality traits (Lesch et al 1996a). Preliminary studies suggest that it also influences the risk of developing affective spectrum disorders Lesch 1998, Collier et al 1996a. Progress in 5-HTT gene inactivation (knockout) studies are also changing views of the relevance of adaptive 5-HT uptake function and 5-HT homeostasis in brain development and plasticity as well as processes underlying drug dependence and neurodegeneration (Bengel et al 1998). The complete, and particularly the partial (heterozygous), knockout animal model has the potential to mimick the genetically driven variability of functional 5-HT transporter expression.

Despite rapidly increasing evidence for a potential role of the 5-HTT in the integration of synaptic connections in the mammalian brain during development, adult life, and old age, detailed knowledge of the molecular mechanisms involved in this fine-tuning process is just beginning to emerge. By integrating various strategies, including molecular genetic, transgenic, and gene transfer techniques, effort is currently being aimed at elucidating the role of the 5-HTT in neural development, plasticity, and degeneration as well as in disorders of the affective spectrum, neurodevelopment, and neurodegeneration.

Section snippets

Allelic variation in functional 5-HTT expression

The human and murine 5-HTT genes (SLC6A4) are located on chromosome 17 and chromosome 11, respectively. Both are composed of 14 exons spanning ∼35 kb and with conservation of the exon/intron organization and, to a lesser extent, the 5′-flanking noncoding as well as regulatory sequences Lesch et al 1994, Bengel et al 1997, Bradley and Blakely 1997. The role of these transcription factor motifs in the regulation of human and murine 5-HTT gene transcription was studied by transfection studies

5-HTT gene locus, anxiety-related traits, and affective spectrum disorders

5-HTT function is dysregulated in a variety of complex behavioral traits and disorders such as depression, bipolar, anxiety, obsessive–compulsive, and neurodegenerative disorders, as well as substance abuse (for review see Ellis and Salmond 1994, Owens and Nemeroff 1994). Since 5-HT uptake capacity remains decreased after recovery, it has been proposed as a trait marker for affective disorder. Twin studies indicate that 5-HT uptake is genetically controlled (Meltzer and Arora 1988), which is

Developmental biology of the 5-HTT: link to autistic disorder?

The 5-HTT is likely to play a central role in the fine-tuning in 5-HT’s morphogenetic activities such as cell proliferation, differentiation, and metamorphosis in the developing mammalian brain Lauder 1993, Azmitia and Whitaker-Azmitia 1997. In mice the 5-HTT gene becomes transcriptionally active at embryonic day E12 when it regulates cranial neural crest migration (Bruning et al 1997). While in adult life 5-HTT expression appears to be restricted to raphe neurons, it has been detected in the

Obsessive–compulsive disorder

While autism is a disorder affecting social, communicative, and imaginative development, its compulsive core characterized by stereotypic complex movements, insistence on singleness, and narrow repetitive interests is thought to be a component of the OCD spectrum. OCD is a relatively common condition, characterized by persistent, unwanted thoughts and ritualistic behaviors. The involvement of a genetic factor in OCD is likely, based on the results of family and twin studies (Rasmussen 1993).

Panic disorder

While evidence for a genetic liability for panic disorder has been obtained in twin as well as family studies, the role for serotonergic neuromodulation in the etiology of panic disorder has been suggested mainly by the observations that increased serotonergic neurotransmission increases anxiety even up to the level of panic attacks in patients with panic disorder (Kahn and Wetzler 1991) and that decreased serotonin uptake is present in patients with anxiety disorder (Iny et al 1994). This

Schizophrenic disorders

The current concept of schizophrenia as a disorder of neurodevelopment also incorporates a dysfunction of serotonergic signaling, which is thought to be mediated via various 5-HT receptors and the 5-HTT. Among the various 5-HT receptors, however, no consistent association with schizophrenia was detectable at the molecular level, and the reported association of schizophrenia with a silent polymorphism within the coding region of the 5-HT_2A receptor gene requires replication in a family-based

Late-onset Alzheimer’s disease

Disturbances in functional 5-HTT expression are also likely to play a role in the pathophysiology of neurodegenerative disorders. There is considerable evidence indicating an extensive loss of both cholinergic and 5-HT neurons in the brain of patients with Alzheimer’s disease. For example, cholinergic–serotonergic interactions based on 5-HT_1A or 5-HT_1B receptor-mediated modulation of septal and frontal cholinergic neurons have been suggested to play a central role in learning and memory as well

Alcohol dependence

Alcohol dependence is an etiologically and clinically heterogeneous syndrome caused by complex interaction of genetic and environmental factors. Therefore, the differentiation of psychobiological traits of addictive behavior is of particular importance for the dissection of the complex genetic susceptibility of alcoholism (Lander and Schork 1994). Various typologies of alcohol dependence have been proposed. Impulsive–aggressive behavior and early onset define a subgroup of alcoholics (type 2)

Toxic agents that target the 5-HTT: implications for neurodegeneration

Of particular interest is the mechanism of toxin-induced modification of serotonergic function and its impact on brain development, experience-related synaptic plasticity, and neurodegeneration Lesch et al 1996b, Lesch 1998. While tri- and heterocyclic antidepressants inhibit 5-HT reuptake, several agents enhance serotonergic neurotransmission by facilitating both exocytic and nonexocytic 5-HTT transporter-mediated 5-HT release. Amphetamines and their highly lipophilic, neurotoxic analogs, such

Targeted inactivation of the 5-HTT gene

Among the prime transgenic strategies directed at elucidating the role of the 5-HTT in normal behavior and in disease states was the generation of a mouse model with a targeted disruption of the 5-HTT gene. This approach addresses the question: To what extent does targeted disruption of the 5-HTT gene affect biochemistry, electrophysiology, and pharmacology of the 5-HT system and modulate neural development and synaptic plasticity? For generation of 5-HTT-deficient mice a genomic segment

The 5-HT system: target for gene transfer strategies?

Aging, cognitive dysfunction, and neurodegenerative disorders are a principal health concern in the western world, contributing to substantial morbidity and mortality among millions of individuals. No currently available medication effectively combats this problem. Given the fact that the 5-HTT continues to be an important target for large-scale drug production and development, novel therapeutic strategies aiming at 5-HTT gene transcription are currently being explored. The 5-HTT gene promoter

Acknowledgements

KPL is supported by the Hermann and Lilly Schilling Foundation.

This work was presented at the Neuroscience Discussion Forum “A Decade of Serotonin Research” held at Amelia Island, Florida in November 1997. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided by Eli Lilly and Company.

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A Decade of Serotonin ResearchGenetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders?

Abstract

Introduction

Section snippets

Allelic variation in functional 5-HTT expression

5-HTT gene locus, anxiety-related traits, and affective spectrum disorders

Developmental biology of the 5-HTT: link to autistic disorder?

Obsessive–compulsive disorder

Panic disorder

Schizophrenic disorders

Late-onset Alzheimer’s disease

Alcohol dependence

Toxic agents that target the 5-HTT: implications for neurodegeneration

Targeted inactivation of the 5-HTT gene

The 5-HT system: target for gene transfer strategies?

Acknowledgements

Neuron

Trends Pharmacol Sci

Biol Psychiatry

Neuropharmacology

Neuropsychopharmacology

Biol Psychiatry

Neuroscience

Trends Neurosci

Neuron

Biol Psychiatry

Trends Neurosci

Psychiatry Res

Lancet

Intact coding region of the serotonin transporter in obsessive-compulsive disorder

Am J Med Genet

The hyperserotonemia of autism

Ann NY Acad Sci

Development and adult plasticity of serotonergic neurons and their target cells

Serotonin internalizes ApCAMs as an early step of learning-related synaptic growth in aplysia

Science

Autism as a strongly genetic disorderEvidence from a British twin study

Psychol Med

The serotonin transporter gene and peer-rated neuroticism

Neuroreport

Gene structure and 5′-flanking regulatory region of the murine serotonin transporter

Mol Brain Res

Altered brain serotonin (5-HT) homeostasis and locomoter insensitivity to MDMA (“ecstasy”) in 5-HT transporter-deficient mice

Mol Pharmacol

Obsessive compulsive disorder, response to serotonin reuptake inhibitors and the serotonin transporter gene

Mol Psychiatry

Molecular physiology of norepinephrine and serotonin transporters

J Exp Biol

Current psychiatric uses of drugs acting on the serotonin system

Genes, environment and personality

Science

Alternative splicing of the human serotonin transporter gene

J Neurochem

Prenatal development of the serotonin transporter in mouse brain

Cell Tissue Res

Evolutionary personality psychology

Annu Rev Psychol

Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA

Science

A functional neuroanatomy of anxiety and fearImplications for the pathophysiology and treatment of anxiety disorders

Crit Rev Neurobiol

Neurogenetic adaptive mechanisms in alcoholism

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A novel functional polymorphism within the promoter of the serotonin transporter genePossible role in susceptibility to affective disorders

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The serotonin transporter is a potential susceptibility factor for bipolar affective disorder

Neuroreport

Evidence of linkage between the serotonin transporter and autistic disorder

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Psychiatr Genet

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Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in African- and European-American and Japanese populations and in alcohol-dependent subjects

A Decade of Serotonin Research
Genetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders?