The 5-HT1A receptor plays a critical role in the pathophysiology of anxiety and depression as well as in the mode of action of anxiolytic and antidepressant drugs. Human 5-HT1A gene transcription is modulated by a common C-1016G single nucleotide polymorphism (SNP) in its upstream regulatory region. In the present study, we evaluated the role of the HTR1A-1019 polymorphism in the modulation of individual differences in personality traits by an association study of a sample of healthy volunteers. Personality traits were assessed with two different methods, NEO personality inventory (NEO-PI-R) and Tridimensional Personality Questionnaire (TPQ). There was a significant effect of the HTR1A-1019 polymorphism on NEO Neuroticism with carriers of the G allele showing higher scores than individuals homozygous for the C variant. The effect was primarily due to associations with the Neuroticism facets Anxiety and Depression. Carriers of the G allele also exhibited higher TPQ Harm Avoidance scores. Our findings indicate a role of allelic variation in 5-HT1A receptor expression in the development and modulation of anxiety- and depression-related personality traits.

These findings implicate deficits in neuronal signaling via nitric oxide in moderation of prefrontal circuits underlying impulsivity-related behavior in humans.

The relative contribution of the two tryptophan hydroxylase (TPH) isoforms, TPH1 and TPH2, to brain serotonergic system function is controversial. To investigate the respective role of TPH2 in neuron serotonin (5-HT) synthesis and the role of 5-HT in brain development, mice with a targeted disruption of Tph2 were generated. The preliminary results indicate that in Tph2 knockout mice raphe neurons are completely devoid of 5-HT, whereas no obvious alteration in morphology and fiber distribution are observed. The findings confirm the exclusive specificity of Tph2 in brain 5-HT synthesis and suggest that Tph2-synthesized 5-HT is not required for serotonergic neuron formation.

Autism, a pervasive developmental disorder with profound deficits in social relatedness, impairments in language and communication, and symptoms involving repetitive behaviors and restricted interests, is thought to be gene-dependent. 1-3 The well-replicated, but as yet unexplained, platelet hyperserotonemia of autism 4,5 has focused attention on the possible role of the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Reports of other 5-HT-related abnormalities in autism 6,7 and the utility of serotonergic agents in partially ameliorating symptoms in some individuals with autism 8 have also served to increase interest in the possible involvement of 5-HT in the etiology and pathophysiology of autism. The important roles of 5-HT in neurodevelopment 9,10 and the rich serotonergic innervation of limbic areas critically involved in social and affiliative behaviors 11 have provided additional, more theoretical, bases for the 5-HT hypothesis.A wide range of 5-HT-related genes can be considered as possible candidate genes in autism. However, the 5-HT transporter gene (HTT, locus SLC6A4), encoding both the neuronal and platelet transporter, 12 is of particular interest for several reasons. Reports of a positive correlation between rates of platelet 5-HT transport and platelet levels of 5-HT 13,14 suggest that the transporter may play a part in the platelet hyperserotonemia of autism. The beneficial effects of agents that block neuronal serotonin transport 8 also focus attention on the possible role of the transporter in the pathophysiology of autism. Additionally, the reported association of a HTT promoter polymorphism with anxiety in the general population, 15 coupled with reports of higher stress responsivity in autism and an increased incidence of anxiety disorder in the families of individuals with autism, 16,17 has further stimulated interest in the HTT in autism. Most intriguing have been discrepant studies reporting preferential transmission of different alleles of the biallelic promoter region polymorphism in individuals with autism. 18,19 The promoter variant consists of a 44 base-pair deletion/insertion in a repeat region of the promoter. The deletion or short (s) allele occurs with a frequency of approximately 43%, while the long (l) form has an allele frequency of 57% in samples of predominately northern European ancestry. 15,20 It is noteworthy that the polymorphism is of apparent functional significance; native lymphoblastoid cell lines with sl or ss genotypes were reported to have approximately onehalf the rates of 5-HT transport, transporter expression, and HTT mRNA levels as those with the ll genotype. 15 After genotyping the HTT promoter alleles in a group of 69 French families with autistic children, the transmission of the alleles was examined to determine their influence on risk or susceptibility to autism. A possible modifying role of the HTT on the behavioral phenotypic expression of autism was also studied. This possibility was examined by comparing allelic transmission across severity sub...

No abstract

No abstract

The tryptophan hydroxylase-2 gene (TPH2) codes for the enzyme of serotonin (5-HT) synthesis in the brain and variation of TPH2 has been implicated in disorders of emotion regulation. Here, we used functional magnetic resonance imaging (fMRI) to demonstrate that a potentially functional variant of TPH2 modulates amygdala responsiveness to emotional stimuli of both negative and positive valence.

Brain serotonin (5-HT) is implicated in a wide range of functions from basic physiological mechanisms to complex behaviors, including neuropsychiatric conditions, as well as in developmental processes. Increasing evidence links 5-HT signaling alterations during development to emotional dysregulation and psychopathology in adult age. To further analyze the importance of brain 5-HT in somatic and brain development and function, and more specifically differentiation and specification of the serotonergic system itself, we generated a mouse model with brain-specific 5-HT deficiency resulting from a genetically driven constitutive inactivation of neuronal tryptophan hydroxylase-2 (Tph2). Tph2 inactivation (Tph2−/−) resulted in brain 5-HT deficiency leading to growth retardation and persistent leanness, whereas a sex- and age-dependent increase in body weight was observed in Tph2+/− mice. The conserved expression pattern of the 5-HT neuron-specific markers (except Tph2 and 5-HT) demonstrates that brain 5-HT synthesis is not a prerequisite for the proliferation, differentiation and survival of raphe neurons subjected to the developmental program of serotonergic specification. Furthermore, although these neurons are unable to synthesize 5-HT from the precursor tryptophan, they still display electrophysiological properties characteristic of 5-HT neurons. Moreover, 5-HT deficiency induces an up-regulation of 5-HT1A and 5-HT1B receptors across brain regions as well as a reduction of norepinephrine concentrations accompanied by a reduced number of noradrenergic neurons. Together, our results characterize developmental, neurochemical, neurobiological and electrophysiological consequences of brain-specific 5-HT deficiency, reveal a dual dose-dependent role of 5-HT in body weight regulation and show that differentiation of serotonergic neuron phenotype is independent from endogenous 5-HT synthesis.