New lessons from knockout mice: The role of serotonin during development and its possible contribution to the origins of neuropsychiatric disorders.
TL;DR: Serotonergic dysfunction has been implicated in several neuropsychiatric conditions but efforts to more clearly understand the mechanisms of this influence have been hampered by the complexity of this system at the receptor level.
Abstract: Serotonin (5-HT) modulates numerous processes in the central nervous system that are relevant to neuropsychiatric function and dysfunction. It exerts significant effects on anxiety, mood, impulsivity, sleep, ingestive behaviors, reward systems, and psychosis. Serotonergic dysfunction has been implicated in several neuropsychiatric conditions but efforts to more clearly understand the mechanisms of this influence have been hampered by the complexity of this system at the receptor level. There are at least 14 distinct receptors that mediate the effects of 5-HT as well as several enzymes that control its synthesis and metabolism. Pharmacologic agents that target specific receptors have provided clues regarding the function of these receptors in the adult brain. 5-HT is also an important modulator of neural development and several groups have employed a genetic strategy to ablate specific components of the 5-HT system in order to understand the role of different serotonergic in development of brain systems relevant to behavior. Several inactivation mutations of specific 5-HT receptors have been generated producing interesting behavioral phenotypes related to anxiety, depression, drug abuse, psychosis, and cognition. In many cases, knockout mice have been used to confirm what has already been suspected based on pharmacologic studies. In other instances, mutations have demonstrated new functions of serotonergic genes in development and behavior.
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TL;DR: A critical role of serotonin in the maturation of brain systems that modulate emotional function in the adult is indicated and a developmental mechanism to explain how low-expressing 5-HTT promoter alleles increase vulnerability to psychiatric disorders is suggested.
Abstract: Reduced serotonin transporter (5-HTT) expression is associated with abnormal affective and anxiety-like symptoms in humans and rodents, but the mechanism of this effect is unknown. Transient inhibition of 5-HTT during early development with fluoxetine, a commonly used serotonin selective reuptake inhibitor, produced abnormal emotional behaviors in adult mice. This effect mimicked the behavioral phenotype of mice genetically deficient in 5-HTT expression. These findings indicate a critical role of serotonin in the maturation of brain systems that modulate emotional function in the adult and suggest a developmental mechanism to explain how low-expressing 5-HTT promoter alleles increase vulnerability to psychiatric disorders.
800 citations
TL;DR: This is the first demonstration that oxytocin may regulate serotonin release and exert anxiolytic effects via direct activation of Oxytocin receptor expressed in serotonergic neurons of the raphe nuclei.
Abstract: The oxytocin receptor has been implicated in the regulation of reproductive physiology as well as social and emotional behaviors. The neurochemical mechanisms by which oxytocin receptor modulates social and emotional behavior remains elusive, in part because of a lack of sensitive and selective antibodies for cellular localization. To more precisely characterize oxytocin receptor-expressing neurons within the brain, we generated an oxytocin receptor-reporter mouse in which part of the oxytocin receptor gene was replaced with Venus cDNA (a variant of yellow fluorescent protein). Examination of the Venus expression revealed that, in the raphe nuclei, about one-half of tryptophan hydroxylase-immunoreactive neurons were positive for Venus, suggesting a potential role for oxytocin in the modulation of serotonin release. Oxytocin infusion facilitated serotonin release within the median raphe nucleus and reduced anxiety-related behavior. Infusion of a 5-HT 2A/2C receptor antagonist blocked the anxiolytic effect of oxytocin, suggesting that oxytocin receptor activation in serotonergic neurons mediates the anxiolytic effects of oxytocin. This is the first demonstration that oxytocin may regulate serotonin release and exert anxiolytic effects via direct activation of oxytocin receptor expressed in serotonergic neurons of the raphe nuclei. These results also have important implications for psychiatric disorders such as autism and depression in which both the oxytocin and serotonin systems have been implicated.
504 citations
Cites background from "New lessons from knockout mice: The..."
...Both OXT and serotonin play an important role in neural development (Whitaker-Azmitia, 2001; Gross et al., 2002; Carter, 2003; Gingrich et al., 2003)....
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TL;DR: The rationale for studying genetic effects on brain function with neuroimaging is outlined and studies of genetically driven variation in serotonin transporter function on corticolimbic structure and function are used to highlight the effectiveness of this strategy to delineate biological pathways and mechanisms by which individual differences in brain function emerge and potentially bias behavior and risk for psychiatric illness.
336 citations
TL;DR: A critical role of Lmx1b is revealed in maintaining the differentiated status of 5-HT neurons in mice with normal locomotor function, and the expression of Pet1 is tightly coupled with expression of L MX1b during later stages of embryonic development, indicating that LMX1b maintains Pet1 expression.
Abstract: Central serotonergic neurons have been implicated in numerous animal behaviors and psychiatric disorders, but the molecular mechanisms underlying their development are not well understood Here we generated Lmx1b (LIM homeobox transcription factor 1 β) conditional knock-out mice ( Lmx1bf/f/p ) in which Lmx1b was only deleted in Pet1 (pheochromocytoma 12 ETS factor-1)-expressing 5-HT neurons In Lmx1bf/f/p mice, the initial generation of central 5-HT neurons appeared normal However, the expression of both 5-HT-specific and non-5-HT-specific markers was lost in these neurons at later stages of development The loss of gene expression is concomitant with downregulation of Lmx1b expression, with the exception of serotonin transporter Sert and tryptophan hydroxylase TPH2 , whose expression appears to be most sensitive to Lmx1b Interestingly, the expression of Pet1 is tightly coupled with expression of Lmx1b during later stages of embryonic development, indicating that Lmx1b maintains Pet1 expression In Lmx1bf/f/p mice, almost all central 5-HT neurons failed to survive Surprisingly, Lmx1bf/f/p mice survived to adulthood and exhibited normal locomotor activity These data reveal a critical role of Lmx1b in maintaining the differentiated status of 5-HT neurons Lmx1bf/f/p mice with normal locomotor function should provide a unique animal model for examining the roles of central 5-HT in a variety of animal behaviors
201 citations
Cites background from "New lessons from knockout mice: The..."
...…studies, especially those originating from phenotypic analysis of 5-HT receptor knock-out mice, have highlighted the important role of the 5-HT system in modulating many developmental processes and psychiatric functions (Scearce-Levie et al., 1999; Gaspar et al., 2003; Gingrich et al., 2003)....
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...In this context, recent genetic studies, especially those originating from phenotypic analysis of 5-HT receptor knock-out mice, have highlighted the important role of the 5-HT system in modulating many developmental processes and psychiatric functions (Scearce-Levie et al., 1999; Gaspar et al., 2003; Gingrich et al., 2003)....
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TL;DR: Although the predominant role of the central 5-HT system in inflammatory pain is inhibitory, its role in acute mechanical pain is facilitatory, and the analgesic actions of the SNRI duloxetine and the SSRI fluoxettine were differentially affected.
Abstract: A large body of literature has implicated serotonin [5-hydroxytryptamine (5-HT)] in descending modulation of nociceptive transmission. Here, we have studied the pain behavior of Lmx1b conditional knock-out mice (Lmx1b(f/f/p)), which lack 5-HT neurons in the CNS. Lmx1b(f/f/p) mutant mice showed normal thermal and visceral pain responses but were less sensitive to mechanical stimuli and exhibited enhanced inflammatory pain compared with their littermate control mice. Importantly, the analgesic effect of several antidepressant drugs, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants, was either abolished or greatly attenuated in Lmx1b(f/f/p) mice. Moreover, in the acute versus persistent pain settings, the analgesic actions of the SNRI duloxetine and the SSRI fluoxetine were differentially affected. Together, our results provide in vivo genetic evidence demonstrating that although the predominant role of the central 5-HT system in inflammatory pain is inhibitory, its role in acute mechanical pain is facilitatory. The findings that the analgesic effects of various antidepressant drugs are differentially dependent on the central 5-HT system should help us to understand the mechanism of the analgesic action of different classes of antidepressants in the management of persistent pain.
134 citations
Cites background from "New lessons from knockout mice: The..."
...Does plasticity play a role in pain behaviors of Lmx1b mice? Pain is intimately associated with other behavioral states that are likely to be regulated by 5-HT neurons (Mason, 2001; Gingrich et al., 2003)....
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...Pain is intimately associated with other behavioral states that are likely to be regulated by 5-HT neurons (Mason, 2001; Gingrich et al., 2003)....
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References
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TL;DR: The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5HTT expression and 5HT uptake in lymphoblasts as discussed by the authors, which is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs.
Abstract: Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.
5,072 citations
"New lessons from knockout mice: The..." refers background in this paper
...The low-expressing SERT variant has also been associated with high levels of trait anxiety on the Neuroticism, Extroversion, and Openness questionnaire.(4) Hariri and colleagues(11) demonstrated that individuals with either one or two copies of the short promoter variant exhibited higher levels of amygdala activation in response to fearful stimuli....
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...A similar example can be found in human subjects possessing a "short" variant of the serotonin transporter (SERT) promoter region that is reported to reduce SERT expression by approximately half.(4) Human subjects possessing the short promoter variant have been reported to exhibit increased vulnerability to affective disorders and suicide in certain populations....
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TL;DR: In this paper, a large sample of male children from birth to adulthood was studied to determine why some children who are maltreated grow up to develop antisocial behavior, whereas others do not.
Abstract: We studied a large sample of male children from birth to adulthood to determine why some children who are maltreated grow up to develop antisocial behavior, whereas others do not. A functional polymorphism in the gene encoding the neurotransmitter-metabolizing enzyme monoamine oxidase A (MAOA) was found to moderate the effect of maltreatment. Maltreated children with a genotype conferring high levels of MAOA expression were less likely to develop antisocial problems. These findings may partly explain why not all victims of maltreatment grow up to victimize others, and they provide epidemiological evidence that genotypes can moderate children's sensitivity to environmental insults.
4,151 citations
TL;DR: Genetically driven variation in the response of brain regions underlying human emotional behavior is demonstrated and differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele.
Abstract: A functional polymorphism in the promoter region of the human serotonin transporter gene (SLC6A4) has been associated with several dimensions of neuroticism and psychopathology, especially anxiety traits, but the predictive value of this genotype against these complex behaviors has been inconsistent. Serotonin [5- hydroxytryptamine, (5-HT)] function influences normal fear as well as pathological anxiety, behaviors critically dependent on the amygdala in animal models and in clinical studies. We now report that individuals with one or two copies of the short allele of the serotonin transporter (5-HTT) promoter polymorphism, which has been associated with reduced 5-HTT expression and function and increased fear and anxiety-related behaviors, exhibit greater amygdala neuronal activity, as assessed by BOLD functional magnetic resonance imaging, in response to fearful stimuli compared with individuals homozygous for the long allele. These results demonstrate genetically driven variation in the response of brain regions underlying human emotional behavior and suggest that differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele.
2,248 citations
TL;DR: Analytical results indicate that isolated complete MAOA deficiency in this family is associated with a recognizable behavioral phenotype that includes disturbed regulation of impulsive aggression.
Abstract: Genetic and metabolic studies have been done on a large kindred in which several males are affected by a syndrome of borderline mental retardation and abnormal behavior. The types of behavior that occurred include impulsive aggression, arson, attempted rape, and exhibitionism. Analysis of 24-hour urine samples indicated markedly disturbed monoamine metabolism. This syndrome was associated with a complete and selective deficiency of enzymatic activity of monoamine oxidase A (MAOA). In each of five affected males, a point mutation was identified in the eighth exon of the MAOA structural gene, which changes a glutamine to a termination codon. Thus, isolated complete MAOA deficiency in this family is associated with a recognizable behavioral phenotype that includes disturbed regulation of impulsive aggression.
1,481 citations
"New lessons from knockout mice: The..." refers background in this paper
...This finding may suggest that serotonergic function may also play a role in the mechanism of action of this important class of anxiolytics.(1) AKO mice have also been found to be insensitive to the effects of fluoxetine in the novelty-suppressed feeding test—one of the few animal tests that appears to model anxiolytic effects of SSRIs....
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...One clear example comes from the study of a Dutch family that was found to have congenital deficiency of the monoamine oxidase A (MAOA) gene.(1) The male members of this family were notable for increased levels of impulsive violence, including arson, rape, and murder....
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...The male members of this family were notable for increased levels of impulsive violence, including arson, rape, and murder.(1) The behavioral consequences of this mutations are strikingly different from those produced by pharmacologic inhibition of MAOA....
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TL;DR: Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine, and adults manifested a distinct behavioral syndrome, including enhanced aggression in males.
Abstract: Deficiency in monoamine oxidase A (MAOA), an enzyme that degrades serotonin and norepinephrine, has recently been shown to be associated with aggressive behavior in men of a Dutch family. A line of transgenic mice was isolated in which transgene integration caused a deletion in the gene encoding MAOA, providing an animal model of MAOA deficiency. In pup brains, serotonin concentrations were increased up to ninefold, and serotonin-like immunoreactivity was present in catecholaminergic neurons. In pup and adult brains, norepinephrine concentrations were increased up to twofold, and cytoarchitectural changes were observed in the somatosensory cortex. Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine. Adults manifested a distinct behavioral syndrome, including enhanced aggression in males.
1,165 citations