Spatio-temporal expression of tryptophan hydroxylase isoforms in murine and human brain: Convergent data from Tph2 knockout mice

Gutknecht, Lise; Kriegebaum, C.; Waider, Jonas; Schmitt, Angelika; Lesch, Klaus‐Peter

doi:10.1016/j.euroneuro.2008.12.005

Cited by 148 publications

(129 citation statements)

References 42 publications

Supporting

Mentioning

122

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, there were no changes in TPH2 expression and activity or 5-HT and 5-HIAA levels in terminal regions. While 5-HT synthesis in the cell bodies of 5-HT neurons supplies local 5-HT release in the midbrain, 5-HT released in the projection areas of 5-HT neurons is synthesized in the terminals (Carkaci-Salli et al, 2011;Gutknecht et al, 2009). A dissociation of TPH2 activity in cell body and terminal regions has been reported previously (Browne et al, 2011) suggesting differential regulation of TPH2 for somatodendritic 5-HT release in the raphe nuclei or for axonal/synaptic release in the innervated brain areas.…”

Section: Mechanisms Underlying the Behavioral Phenotypementioning

confidence: 90%

Adult AMPA GLUA1 Receptor Subunit Loss in 5-HT Neurons Results in a Specific Anxiety-Phenotype with Evidence for Dysregulation of 5-HT Neuronal Activity

Weber

Vogt

Gartside

et al. 2014

Neuropsychopharmacol

View full text Add to dashboard Cite

Both the glutamatergic and serotonergic (5-HT) systems are implicated in the modulation of mood and anxiety. Descending cortical glutamatergic neurons regulate 5-HT neuronal activity in the midbrain raphe nuclei through a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. To analyze the functional role of GLUA1-containing AMPA receptors in serotonergic neurons, we used the Cre-ERT2/loxP-system for the conditional inactivation of the GLUA1-encoding Gria1 gene selectively in 5-HT neurons of adult mice. These Gria1 5-HT À / À mice exhibited a distinct anxiety phenotype but showed no alterations in locomotion, depression-like behavior, or learning and memory. Increased anxiety-related behavior was associated with significant decreases in tryptophan hydroxylase 2 (TPH2) expression and activity, and subsequent reductions in tissue levels of 5-HT, its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine in the raphe nuclei. However, TPH2 expression and activity as well as monoamine levels were unchanged in the projection areas of 5-HT neurons. Extracellular electrophysiological recordings of 5-HT neurons revealed that, while a1-adrenoceptor-mediated excitation was unchanged, excitatory responses to AMPA were enhanced and the 5-HT 1A autoreceptor-mediated inhibitory response to 5-HT was attenuated in Gria1 5-HT À / À mice. Our data show that a loss of GLUA1 protein in 5-HT neurons enhances AMPA receptor function and leads to multiple local molecular and neurochemical changes in the raphe nuclei that dysregulate 5-HT neuronal activity and induce anxiety-like behavior.

show abstract

Section: Mechanisms Underlying the Behavioral Phenotypementioning

confidence: 90%

Adult AMPA GLUA1 Receptor Subunit Loss in 5-HT Neurons Results in a Specific Anxiety-Phenotype with Evidence for Dysregulation of 5-HT Neuronal Activity

Weber

Vogt

Gartside

et al. 2014

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…While mice with a constitutive Lmx1b inactivation are not viable, in conditional Lmx1b KO (cKO) mice, in which the gene deletion is driven specifically in 5-HT neurons, these neurons are generated but fail to differentiate and survive. In contrast, in Tph2 2/2 mice, raphe neurons and their projections, although devoid of Tph2 and 5-HT, are morphologically and functionally preserved [11,14].…”

Section: Tph2 In Personality Traits Of Negative Emotionality and In Dmentioning

confidence: 93%

“…Very low brain 5-HT levels were also detected in other Tph2 2/2 mice [21] as well as in Tph1/Tph2 2/2 double KO mice [23]. In addition, we previously showed that Tph1 is not upregulated in Tph2 2/2 brain, indicating that Tph1-driven 5-HT synthesis can be ruled out in the brain [11]. However, there are several alternative explanations: (i) HPLC does not detect 5-HT but a closely related compound with the same retention time, a possibility to be resolved by mass spectrometry, (ii) the immediate 5-HT precursor (5-HTP) produced by peripheral Tph1 crosses the blood-brain barrier and could be transformed into 5-HT because AADC is ubiquitously expressed, (iii) other enzymes, such as phenylalanine hydroxylase, or as yet unknown enzymes, use tryptophan as substrate and produce 5-HT, and (iv) alternative metabolic pathways are able to produce 5-HTas end-or by-product.…”

Section: (C) Monoamine Transmitters and Neuronsmentioning

confidence: 94%

“…(b) Specification of raphe neurons lacking 5-HT synthesis Several in vitro studies showed a morphogenic effect of 5-HT on proliferation, differentiation, migration and survival of neural cells [80][81][82] 11,14). Conserved particularly is the expression of genes specifying a serotonergic phenotype in raphe neurons lacking 5-HT synthesis.…”

Section: Tph2 In Personality Traits Of Negative Emotionality and In Dmentioning

confidence: 99%

“…Tph2 is specifically expressed in the serotonergic neurons of the brainstem raphe complex and is exclusively responsible for the 5-HT synthesis within the brain, whereas Tph1 is the peripheral isoform [11]. The gene encoding TPH2 is located on human chromosome 12q21.1 and was mapped to chromosome 10D1 in the mouse, respectively.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

Lesch

Araragi

Waider

et al. 2012

Phil. Trans. R. Soc. B

Self Cite

128

View full text Add to dashboard Cite

Aggression, which comprises multi-faceted traits ranging from negative emotionality to antisocial behaviour, is influenced by an interaction of biological, psychological and social variables. Failure in social adjustment, aggressiveness and violence represent the most detrimental long-term outcome of neurodevelopmental disorders. With the exception of brain-specific tryptophan hydroxylase-2 (Tph2), which generates serotonin (5-HT) in raphe neurons, the contribution of gene variation to aggression-related behaviour in genetically modified mouse models has been previously appraised (Lesch 2005 Novartis Found Symp. 268, 111 -140; Lesch & Merschdorf 2000 Behav. Sci. Law 18, 581 -604). Genetic inactivation of Tph2 function in mice led to the identification of phenotypic changes, ranging from growth retardation and late-onset obesity, to enhanced conditioned fear response, increased aggression and depression-like behaviour. This spectrum of consequences, which are amplified by stress-related epigenetic interactions, are attributable to deficient brain 5-HT synthesis during development and adulthood. Human data relating altered TPH2 function to personality traits of negative emotionality and neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation are based on genetic association and are therefore not as robust as the experimental mouse results. Mouse models in conjunction with approaches focusing on TPH2 variants in humans provide unexpected views of 5-HT's role in brain development and in disorders related to negative emotionality, aggression and antisocial behaviour.Keywords: tryptophan hydroxylase (TPH2); cognition; emotion; impulsivity; aggression; violence INTRODUCTIONNegative emotionality, aggression and antisociality are complex temperamental traits and social behaviours that arise out of multiple causes involving biological and psychological dynamisms and social forces, and different forms of emotional behaviour may each result from different biopsychosocial pathways. The societal implications of aggressiveness, which results in numerous facets of aggressive behaviour and ranges from the establishment of hierarchies and dominance to antisocial behaviour and delinquency, have been examined with preclinical and clinical frameworks.Developmentally inappropriate conduct, aggressiveness and failure in social adjustment represent the most detrimental and harmful long-term outcome of a wide spectrum of neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation.In both humans and animals, the term aggression comprises a variety of behaviours that are heterogeneous for clinical phenomenology and neurobiological features. While the impact of complex cultural variables on behaviour impedes simple extrapolation of animal phenotypes to human traits, clinical observation, experimental paradigms in the laboratory and cluster/ factor-analytic statistics have been used in attempts to subdivide aggression. On the basis of different approaches, hu...

show abstract

The Genetics of Human Aggressive Behaviour

Craig

Halton

2010

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

Both genes and environment contribute to individual differences in aggression. Surveys of the pathways implicated in the physiological and neuronal processes involved highlight the potential role of genes regulating sexual differentiation, anxiety, stress response and neurotransmission. To date, however, association studies have provided little evidence of a substantially significant role for any single candidate gene in such pathways. This may be because genes function against a background in which other genetic and environmental factors are crucial. A series of recent studies, particularly concentrating on monoamine oxidase A , has emphasised the necessity of examining gene by environmental interactions if the contributions of individual loci are to be understood. These findings have major significance for the interpretation of data, both from individual gene and whole genome association studies. Functional imaging studies of genetic variants affecting serotonin pathways have also provided valuable insights into potential links between genes, brain and aggressive behaviour. Key Concepts: Aggression is an evolutionarily advantageous trait with input from one of the most primitive brain regions, the amygdala. There is significant disparity between aggressive behaviour in males and females. Genes and environment both influence aggressive behaviour and there is evidence that stressful life events can interact with specific genetic variants. DBH , COMT , adrenergic receptors, NET1 and SLC6A2 have been studied as possible candidate genes linking stress and aggression. In the serotonin system, genetic polymorphisms in MAOA , SLC6A4 , TPH1/2 and the serotonin receptor genes have been linked with aggression. Studies have shown a potential link between diet and its effects (e.g. on glucose levels) and aggression. Brain imaging studies are beginning to assist an interpretation of the links between genetic variation and aggression.

show abstract

Spatio-temporal expression of tryptophan hydroxylase isoforms in murine and human brain: Convergent data from Tph2 knockout mice

Cited by 148 publications

References 42 publications

Adult AMPA GLUA1 Receptor Subunit Loss in 5-HT Neurons Results in a Specific Anxiety-Phenotype with Evidence for Dysregulation of 5-HT Neuronal Activity

Adult AMPA GLUA1 Receptor Subunit Loss in 5-HT Neurons Results in a Specific Anxiety-Phenotype with Evidence for Dysregulation of 5-HT Neuronal Activity

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

The Genetics of Human Aggressive Behaviour

Contact Info

Product

Resources

About