Characterizing the metabolomic signature of attention-deficit hyperactivity disorder in twins.

Emerging evidence implicate the gut microbiota as a potential susceptibility factor in attention-deficit hyperactivity disorder (ADHD), a common multifactorial neurodevelopmental condition. However, little is known about the biochemical signature of ADHD, including the metabolic contribution of the microbiota via the gut-brain axis, and the relative contribution of genetics and environmental factors. Here, we perform unbiased metabolomic profiling of urine and fecal samples collected from a well-characterized Swedish twin cohort enriched for ADHD (33 ADHD, 79 non-ADHD), using 1H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry. Our results highlight sex-specific patterns in the metabolic phenotype of individuals with ADHD. Specifically, the urine profile of males, but not females, with ADHD was characterized by greater excretion of hippurate, a product of microbial-host co-metabolism that can cross the blood-brain-barrier with bioactivity of potential relevance to ADHD. This trans-genomic metabolite was also negatively correlated with IQ in males and was significantly correlated with fecal metabolites associated with gut microbial metabolism. The fecal profile of ADHD individuals was characterized by increased excretion of stearoyl-linoleoyl-glycerol, 3,7-dimethylurate, and FAD and lower amounts of glycerol 3-phosphate, thymine, 2(1H)-quinolinone, aspartate, xanthine, hypoxanthine, and orotate. These changes were independent of ADHD medication, age, and BMI. Furthermore, our specific twins' models revealed that many of these gut metabolites had a stronger genetic influence than environmental. These findings suggest that metabolic disturbances in ADHD, involving combined gut microbial and host metabolic processes, may largely derive from gene variants previously linked to behavioral symptoms in this disorder. This article is part of the Special Issue on "Microbiome & the Brain: Mechanisms & Maladies".

Toll-like receptor-4 regulates anxiety-like behavior and DARPP-32 phosphorylation.

Toll-like receptors (TLRs) play a crucial role in early innate immune responses to inflammatory agents and pathogens. In the brain, some members of the TLR family are expressed in glial cells and neurons. In particular, TLR4 has been involved in learning and memory processes, stress-induced adaptations, and pathogenesis of neurodegenerative disorders. However, the role of TLR4 in emotional behaviors and their underlying mechanisms are poorly understood. In this study, we investigated the role of TLR4 in emotional and social behavior by using different behavioral approaches, and assessed potential molecular alterations in important brain areas involved in emotional responses. TLR4 knockout (KO) mice displayed increased anxiety-like behavior and reduced social interaction compared to wild type control mice. This behavioral phenotype was associated with an altered expression of genes known to be involved in emotional behavior [e.g., brain-derived neurotrophic factor (BDNF) and metabotropic glutamate receptors (mGluRs)]. Interestingly, the mRNA expression of dopamine- and cAMP-regulated phosphoprotein-32 (DARPP-32) was strongly upregulated in emotion-related regions of the brain in TLR4 KO mice. In addition, the phosphorylation levels at Thr75 and Ser97 in DARPP-32 were increased in the frontal cortex of TLR4 KO male mice. These findings indicate that TLR4 signaling is involved in emotional regulation through modulation of DARPP-32, which is a signaling hub that plays a critical role in the integration of numerous neurotransmitter systems, including dopamine and glutamate.

The bacterial peptidoglycan-sensing molecule Pglyrp2 modulates brain development and behavior.

Recent studies have revealed that the gut microbiota modulates brain development and behavior, but the underlying mechanisms are still poorly understood. Here, we show that bacterial peptidoglycan (PGN) derived from the commensal gut microbiota can be translocated into the brain and sensed by specific pattern-recognition receptors (PRRs) of the innate immune system. Using expression-profiling techniques, we demonstrate that two families of PRRs that specifically detect PGN (that is, PGN-recognition proteins and NOD-like receptors), and the PGN transporter PepT1 are highly expressed in the developing brain during specific windows of postnatal development in both males and females. Moreover, we show that the expression of several PGN-sensing molecules and PepT1 in the developing striatum is sensitive to manipulations of the gut microbiota (that is, germ-free conditions and antibiotic treatment). Finally, we used the PGN-recognition protein 2 (Pglyrp2) knockout mice to examine the potential influence of PGN-sensing molecules on brain development and behavior. We demonstrate that the absence of Pglyrp2 leads to alterations in the expression of the autism risk gene c-Met, and sex-dependent changes in social behavior, similar to mice with manipulated microbiota. These findings suggest that the central activation of PRRs by microbial products could be one of the signaling pathways mediating the communication between the gut microbiota and the developing brain.

Genetic variation in dopamine-related gene expression influences motor skill learning in mice.

Several neurodevelopmental disorders with a strong genetic basis, including attention-deficit/hyperactivity disorder, autism spectrum disorders and developmental coordination disorder, involve deficits in fine motor skills. This phenotype may depend on heritable variation in components of the dopamine (DA) system, which is known to play a critical role in motor skill learning. In this study, we took advantage of two inbred strains of mice (BALB/c and C57BL/6) that differ markedly in the number of midbrain DA neurons in order to investigate the influence of such naturally occurring genetic variation on the acquisition and performance of fine motor skills. Gene expression analysis of midbrain, frontal cortex and striatum showed significant differences in the expression of presynaptic and postsynaptic dopaminergic (DAergic) markers (e.g. tyrosine hydroxylase, DA transporter, DA D4 receptor, DA D5 receptor and DARPP-32) between these two strains. BALB/c mice had lower learning rate and performance scores in a complex skilled reaching task when compared with C57BL/6 mice. A negative correlation was found between the motor learning rate and level of DARPP-32 mRNA expression in the frontal cortex contralateral to the trained forelimb. The rate of motor learning was also negatively correlated with the levels of DARPP-32 and DA D1 receptor mRNAs in the striatum. Our results suggest that genetically driven variation in frontostriatal DAergic neurotransmission is a major contributor to individual differences in motor skill learning. Moreover, these findings implicate the D1R/cAMP/DARPP-32 signaling pathway in those neurodevelopmental disorders that are associated with fine motor skill deficits.

[Alterations in the pattern of dopaminergic markers in attention-deficit/hyperactivity disorder]. / Alteraciones de los patrones de los marcadores de la dopaminaen el trastorno por déficit de atención e hiperactividad.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder of childhood onset that can include elements of inattention, hyperactivity and impulsive behavior. It is often treated with stimulant medications such as methylphenidate hydrochloride (MPH). The neurobiology of ADHD is not well understood, but there is converging evidence of the involvement of the catecholamine rich frontal-striatal circuitry. A prominent theory of ADHD is that there is a dysregulation of dopamine neurotransmission in this circuitry. Given support to this theory is the observation from human imaging studies that MPH blocks the dopamine transporter (DAT), the main mechanism for removing dopamine from the synapse; thereby increasing extracellular dopamine levels in the striatum. Genetic and molecular studies have also demonstrated an association between dopamine related genes (e.g., DAT, dopamine D4 and D5 receptors) and ADHD. DEVELOPMENT: Studies using positron emission tomography (PET) and single photon emission tomography indicate alterations in dopamine markers in ADHD. The majority of the existing studies have reported increased DAT binding (ranging between 17 and 70%) in the striatum of both children and adults with ADHD, while a new PET study reported lower DAT binding in the midbrain (where the dopaminergic neurons of the substantia nigra and ventral tegmental area are located) of adolescents with ADHD. Studies using [18F]fluorodopa to assess dopamine synthesis and metabolism have demonstrated abnormalities in presynaptic activity in patients with ADHD; however the nature of these changes appears to be age-dependent. Some limited data also indicate potential alterations in dopamine D2 receptor availability in children with ADHD. CONCLUSIONS: The results from the human brain imaging studies are still not definitive because of discrepancies in the findings. There is a great need to replicate and expand these findings in treatment-naïve patients with ADHD, taking into consideration potential variables such as drug and smoking history, ethnicity, and presence of comorbidity.

Alteraciones de los patrones de los marcadores de la dopamina en el trastorno por déficit de atención e hiperactividad / Alterations in the pattern of dopaminergic markers in attention-deficit/hyperactivity disorder

Introducción. El trastorno por déficit de atención e hiperactividad(TDAH) es un trastorno neuroconductual frecuente que seinicia en la infancia y puede incluir elementos como la inatención,hiperactividad y conducta impulsiva. El tratamiento habitual consisteen la administración de fármacos estimulantes como el metilfenidatoclorhidrato (MPH). El mecanismo neurobiológico del TDAH nose comprende muy bien, pero hay pruebas que coinciden en la implicaciónde los circuitos frontoestriatales ricos en catecolaminas. Unade las teorías más destacadas es que existe un trastorno de la regularizaciónde la transmisión de la dopamina en estos circuitos. Esta teoría se apoya en los resultados de los estudios de imagen realizadosen humanos, en los que se ha observado que el MPH bloquea eltransportador de dopamina (DAT), el principal mecanismo por elcual se elimina la dopamina de las sinapsis; por ello, aumentan losniveles de dopamina extracelulares en el estriado. Estudios genéticosy moleculares han mostrado una asociación importante entre losgenes relacionados con la dopamina (como el DAT, los receptores dedopamina D4 y D5) y el TDAH. Desarrollo. Los estudios con PET ySPECT señalan alteraciones en los marcadores dopaminérgicos enel TDAH. La mayoría de estudios actuales han descrito un incrementoen la fijación de DAT (entre el 17 y el 70%) en el estriado de niñosy adultos con TDAH, mientras que en un estudio reciente realizadocon PET se encontró una fijación de DAT disminuida en el mesencéfalo(donde se ubican las neuronas dopaminérgicas de la sustancianegra y la zona tegmental ventral) de adolescentes con TDAH. Losestudios con [18F]fluorodopa para evaluar la síntesis y el metabolismode la dopamina han mostrado anomalías en la actividad presinápticade pacientes con TDAH; estos cambios parecen depender dela edad. Algunos datos limitados apuntan a alteraciones potencialesen las cantidades de receptor de dopamina D2 disponibles en niñoscon TDAH. Conclusiones. Los resultados de los estudios de imagencon cerebros humanos no son definitivos todavía debido a ciertasdiscrepancias en los hallazgos. Es necesario replicar y ampliar estosresultados en pacientes con TDAH que no han recibido tratamientoprevio, teniendo en cuenta posibles variables como los antecedentesrelacionados con el consumo de drogas y el tabaquismo, la etnicidady la comorbilidad

Introduction. Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder of childhoodonset that can include elements of inattention, hyperactivity and impulsive behavior. It is often treated with stimulantmedications such as methylphenidate hydrochloride (MPH). The neurobiology of ADHD is not well understood, but there isconverging evidence of the involvement of the catecholamine rich frontal-striatal circuitry. A prominent theory of ADHD is thatthere is a dysregulation of dopamine neurotransmission in this circuitry. Given support to this theory is the observation fromhuman imaging studies that MPH blocks the dopamine transporter (DAT), the main mechanism for removing dopamine fromthe synapse; thereby increasing extracellular dopamine levels in the striatum. Genetic and molecular studies have alsodemonstrated an association between dopamine related genes (e.g., DAT, dopamine D4 and D5 receptors) and ADHD.Development. Studies using positron emission tomography (PET) and single photon emission tomography indicate alterationsin dopamine markers in ADHD. The majority of the existing studies have reported increased DAT binding (ranging between 17and 70%) in the striatum of both children and adults with ADHD, while a new PET study reported lower DAT binding in themidbrain (where the dopaminergic neurons of the substantia nigra and ventral tegmental area are located) of adolescents withADHD. Studies using [18F]fluorodopa to assess dopamine synthesis and metabolism have demonstrated abnormalities inpresynaptic activity in patients with ADHD; however the nature of these changes appears to be age-dependent. Some limiteddata also indicate potential alterations in dopamine D2 receptor availability in children with ADHD. Conclusions. The resultsfrom the human brain imaging studies are still not definitive because of discrepancies in the findings. There is a great need toreplicate and expand these findings in treatment-naïve patients with ADHD, taking into consideration potential variables suchas drug and smoking history, ethnicity, and presence of comorbidity

[Biochemical bases and research in attention-deficit hyperactivity disorder]. / Bases bioquímicas e investigaciones en el trastorno por déficit de atención con hiperactividad.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder, which is very common among the school aged population. Its core symptoms are inattention, hyperactivity, and impulsivity. Currently, three principal subtypes of ADHD are recognized: ADHD predominantly inattentive type, ADHD predominantly hyperactive/impulsive type or ADHD combined type. Affected individuals have increased comorbidity risks, often followed by cognitive, emotional and/or social impairments as adults. Stimulants drugs such methylphenidate (Ritalin) or D amphetamine (Dexedrine) represent the first line drugs for the treatment of ADHD. DEVELOPMENT: The clinical features of ADHD were first described by Dr. George Frederick Still for Lancet in 1902, and in spite of the investigations carried out since then, the precise cause is still not clear. The purpose of this review is to describe recent advances of the neurobiological basis of ADHD. CONCLUSIONS: Recent neuroimaging studies in humans indicate a dysfunctions of the frontal striatal circuits in patients with ADHD, which can be improved by pharmacological treatment. Both pre and clinical studies implicate a dysregulation of the dopaminergic and noradrenergic systems, which are known to regulate the functions of these circuits. More recent evidence indicate that some features of ADHD could be linked to alterations in the posterior inferior vermis. These studies also stress the importance of taking into consideration factors such as age, gender and duration of pharmacological treatment when interpreting the results.

Bases bioquímicas e investigaciones en el trastorno por déficit de atención con hiperactividad / Biochemical bases and research in attention-deficit hyperactivity disorder

Introducción. El déficit de atención con hiperactividad (TDAHA) es un trastorno muy común que afecta a alrededor de 37 por ciento de los niños en edad escolar. Desarrollo. Se caracteriza por un desarrollo inapropiado de síntomas de inatención, impulsividad e hiperactividad, que afectan al funcionamiento adecuado del niño. Este tipo de trastorno fue primeramente descrito por el doctor George Still en el 1901, y a pesar de las investigaciones realizadas desde entonces sus causas no se han determinado con exactitud. Conclusión. Esta revisión pretende realizar una puesta al día de las últimas investigaciones en cuanto a las bases neurobiológicas del TDAH; también se abordan aspectos neuroanatómicos, neuroquímicos, y neurorradiológicos de la misma (AU)