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Targeting the murine serotonin transporter: insights into human neurobiology

Key Points

  • Serotonin's suspected involvement in emotions such as anxiety and depression in behavioural and neuropsychiatric disorders, as well as in many physiological processes, has been suggested by indirect evidence over many decades.

  • More recently, specific evidence of a major role for serotonin in human disorders was obtained from evaluations of gene variants, such as the 5-HTTLPR in the gene that encodes the serotonin transporter (SERT), in human lymphoblasts, as well as from studies of post-mortem brain tissue and dynamic brain imaging of SERT.

  • Even stronger evidence of the roles of serotonin and SERT has emerged over the past decade from the use of genetic engineering technologies to produce partially and completely SERT-deficient mice and mice that overexpress SERT.

  • Anxiety-like behaviours and other behaviours, as well as over 50 different changes in brain serotonin homeostasis, have been documented in these mice. These were accompanied by differential responses to anti-anxiety and antidepressant drugs, as well as brain anatomical and physiological changes.

  • Some of these changes are different from those that are produced by selective serotonin reuptake inhibitors (SSRIs; drugs that inhibit SERT and act as antidepressant and anti-anxiety agents when given to adults). Other changes are congruent with the effects of SSRIs that are given early in the postnatal period, helping to confirm that there is a developmental role for many of the changes that are found in mice with genetically altered SERT — especially when gene–environment and gene–gene effects are taken into account.

Abstract

Mutations resulting in reduced or completely abrogated serotonin-transporter (SERT) function in mice have led to the identification of more than 50 different phenotypic changes, ranging from increased anxiety and stress-related behaviours to gut dysfunction, bone weakness and late-onset obesity with metabolic syndrome. These multiple effects, which can be amplified by gene–environment and gene–gene interactions, are primarily attributable to altered intracellular and extracellular serotonin concentrations during development and adulthood. Much of the human data relating to altered expression of the gene that encodes SERT are based on genetic-association findings or correlations and are therefore not as robust as the experimental mouse results. Nevertheless, SERT-function-modifying gene variants in humans apparently produce many phenotypes that are similar to those that manifest themselves in mice.

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Figure 1: Organization of the human serotonin transporter (SERT) gene (SLC6A4).
Figure 2: Molecular manipulations that alter the expression and function of serotonin transporter (SERT) in mice.
Figure 3: Association of age-dependent obesity with increased plasma insulin and leptin in Slc6a4-mutant mice.
Figure 4: Overview of the major pleiotropic central and peripheral phenotypes discovered in Slc6a4−/− and Slc6a4+/− mice.
Figure 5: Central and peripheral serotonergic systems.
Figure 6: Comparison of serotonin-transporter (SERT) expression and function in Slc6a4-mutant mice and in humans with different SLC6A4 5-HTTLPR genotypes.

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Acknowledgements

We thank all of the close associates and friends in our laboratories who contributed to the original reports published during the past 10 years, as well as our colleagues elsewhere who contributed to studies of genetically-engineered Slc6a4-mutant mice, and T. B. DeGuzman for assistance with the manuscript and figures. The authors' related research was supported by the Intramural Research Program of the National Institute of Mental Health (D.L.M.) and by the European Commission (NEWMOOD LSHM-CT-2003-503474), the Bundesministerium für Bildung und Forschung (IZKF 01 KS 9603) and the Deutsche Forschungsgemeinschaft (LE629/4-2, SFB 581, KFO 125) (K.P.L.).

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FURTHER INFORMATION

Dennis L. Murphy's homepage

Klaus-Peter Lesch's homepage

Tabulation of the neurotransmitter sodium symporter (NSS) family

Discussion of reference 1 by K.P.L.

Glossary

Single nucleotide polymorphism

A type of genetic variation within a DNA sequence. It occurs when a single nucleotide (for example, thymine) replaces one of the other three nucleotides (for example, cytosine).

Epigenetics

Structural modifications of chromosomal regions that alter gene activity without changing the nucleotide sequence.

Extinction recall

A unique learning and recall process, mostly studied with fear conditioning, that requires the alteration of stimulus–response associations such that the organism ceases to respond to a previously rewarded stimulus.

Genomic imprinting

For most autosomal genes expression occurs from either allele, whereas a small proportion (<1%) of genes are imprinted, meaning that expression occurs from only one allele. Which of the two alleles is expressed is dependent on the parental origin.

Barrels

Cylindrical columns of neurons that are found in layer IV of the rodent neocortex. Each barrel receives sensory input from a single whisker follicle and the topographical organization of the barrels corresponds precisely to the arrangement of whisker follicles on the face.

Isolated-resident/intruder test

A test for social interaction and offensive aggressive behaviour in rodents. An unfamiliar mouse (the 'intruder') is introduced into the cage of a mouse that has been kept isolated in its 'resident' cage for several months.

Epistasis

A characteristic of the interactions between two or more genetic loci. Negative epistasis occurs when the combined phenotypic effect of two or more loci is less than the sum of the effects at individual loci, whereas positive epistasis occurs when the combined effect of the two or more loci is greater than the sum at individual loci.

Rapid eye movement (REM) sleep

The period of sleep during which dreaming is thought to occur. REM sleep is characterized by increased brain-wave activity, bursts of rapid eye movement, accelerated respiration and heart rate, and muscle relaxation to the point of paralysis.

Serotonin syndrome

An uncommon but potentially life-threatening adverse drug reaction that is caused by excess serotonergic activity at CNS and peripheral serotonin receptors. It can result from intentional self-poisoning, therapeutic drug use or inadvertent interactions between drugs such as SSRIs and monoamine oxidase inhibitors. It can also occur spontaneously in a mild form in Slc6a4−/− mice, and Slc6a4−/− and Slc6a4+/− mice are more susceptible to developing the syndrome following the administration of relatively low doses of many drugs.

Spinal reflexes

Reflex actions that occur relatively quickly because the sensory neurons do not pass directly into the brain; rather, they synapse in the spinal cord. This characteristic bypasses the delay of routing signals through the brain, although the brain does receive sensory input while the reflex action occurs.

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Murphy, D., Lesch, KP. Targeting the murine serotonin transporter: insights into human neurobiology. Nat Rev Neurosci 9, 85–96 (2008). https://doi.org/10.1038/nrn2284

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