Male fire ant neurotransmitter precursors trigger reproductive development in females after mating

Social insect queens have evolved mechanisms to prevent competition from their sexual daughters. For Solenopsis invicta, the fire ant, queens have evolved a primer pheromone that retards reproductive development in their winged reproductive daughters. If these daughters are removed from the influence of the queen, it takes about a week to start reproductive development; however, it starts almost immediately after mating. This dichotomy has been unsuccessfully investigated for several decades. Here we show that male fire ants produce tyramides, derivatives of the biogenic amine tyramine, in their reproductive system. Males transfer tyramides to winged females during mating, where the now newly mated queens enzymatically convert tyramides to tyramine. Tyramine floods the hemolymph, rapidly activating physiological processes associated with reproductive development. Tyramides have been found only in the large Myrmicinae ant sub-family (6,800 species), We suggest that the complex inhibition/disinhibition of reproductive development described here will be applicable to other members of this ant sub-family.

Physiological and Cellular Targets of Neurotrophic Anxiolytic Phytochemicals in Food and Dietary Supplements

Diet impacts anxiety in two main ways. First anxiety can be caused by deficiencies in antioxidants, neurotransmitter precursors, amino acids, cations and vitamins and other cofactors. Second, anxiety can be reduced by anxiolytic nutraceuticals which are food molecules that bind to molecular targets of the amygdala and the hypothalamus-pituitary–adrenal axis (HPA-axis). Anxiety is a feeling of fear that arises from a perceived threat and can be a beneficial coping mechanism to threats and stressors. However excessive anxiety is a disorder that interferes with healthy responses to stressors. The amygdala is responsible for assigning value to a threat or stressor and triggering the HPA-axis to support the body wide system responses to the threat. The amygdala also communicates with the neuroplastic learning and memory centers of the hippocampus to fix or set a learned value to the threat. Interestingly, many anxiolytic nutraceuticals that show benefits in human clinical trials have neurotrophic activity and increase neuronal plasticity. Moreover, anxiolytic nutraceuticals either act like the neurotrophins, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF and neurotrophin-3 (NT3) by either directly binding to or potentiating the tyrosine receptor kinase (TRK) family of receptors (TRKA, TRKB and TRKC) and activating the ERK1/2 signal transduction pathway associated with neurite outgrowth and neural plasticity. This chapter will explore the neuritogenic activity of clinically proven plant-based anxiolytic nutraceuticals and examine the commonality of TRKA-C receptors and the ERK1/2 signaling pathway in the pharmacological and nutraceutical treatment of anxiety disorders.

Gut-Brain Axis Cross-Talk and Limbic Disorders as Biological Basis of Secondary TMAU

Background: Trimethylaminuria (TMAU) is a rare metabolic syndrome characterized by the accumulation and the excretion of trimethylamine (TMA), a volatile diet compound produced by gut microbiota. Gut microbiota alterations are mainly involved in the secondary TMAU, whose patients show also different psychiatric conditions. We hypothesized that the biological activity of several molecules acting as intermediate in TMA metabolic reaction might be at the basis of TMAU psychiatric comorbidities. Methods: To corroborate this hypothesis, we performed the analysis of microbiota of both psychiatric suffering secondary TMAU patients and TMAU “mentally ill” controls, comparing the alteration of metabolites produced by their gut bacteria possibly involved in neurotransmission and, in the same time, belonging to biochemical pathways leading to TMA accumulation. Results: Microbiota analyses showed that Clostridiaceae, Lachnospiraceae and Coriobacteriaceae alterations represented the bacterial families with highest variations. This results in an excessive release of serotonin and an hyperactivation of the vagus nerve that might determine the widest spectrum of psychiatric disorders shown by affected patients. These metabolites, as short chain fatty acids, lactate and neurotransmitter precursors, are also related to TMA accumulation. Conclusions: Knowledge of microbiota-gut-brain axis may become a potential new strategy for improving metabolic diseases and to treat linked psychiatric disorders.

Analysis of Catecholamines and Pterins in Inborn Errors of Monoamine Neurotransmitter Metabolism—From Past to Future

Inborn errors of monoamine neurotransmitter biosynthesis and degradation belong to the rare inborn errors of metabolism. They are caused by monogenic variants in the genes encoding the proteins involved in (1) neurotransmitter biosynthesis (like tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC)), (2) in tetrahydrobiopterin (BH4) cofactor biosynthesis (GTP cyclohydrolase 1 (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), sepiapterin reductase (SPR)) and recycling (pterin-4a-carbinolamine dehydratase (PCD), dihydropteridine reductase (DHPR)), or (3) in co-chaperones (DNAJC12). Clinically, they present early during childhood with a lack of monoamine neurotransmitters, especially dopamine and its products norepinephrine and epinephrine. Classical symptoms include autonomous dysregulations, hypotonia, movement disorders, and developmental delay. Therapy is predominantly based on supplementation of missing cofactors or neurotransmitter precursors. However, diagnosis is difficult and is predominantly based on quantitative detection of neurotransmitters, cofactors, and precursors in cerebrospinal fluid (CSF), urine, and blood. This review aims at summarizing the diverse analytical tools routinely used for diagnosis to determine quantitatively the amounts of neurotransmitters and cofactors in the different types of samples used to identify patients suffering from these rare diseases.

Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment

Neurotransmitter deficiencies are rare neurological disorders with clinical onset during childhood. The disorders are caused by genetic defects in the enzymes involved in synthesis, degradation, or transport of neurotransmitters or by defects in the cofactor biosynthesis such as tetrahydrobiopterin (BH4). With the newly described DNAJC12 deficiency, a chaperon-associated neurotransmitter disorder, the pathophysiological spectrum has been broadened. All deficiencies result in a lack of monoamine neurotransmitters, especially dopamine and its products, with a subset leading to decreased levels of serotonin. Symptoms can occur already in the neonatal period. Classical signs are hypotonia, movement disorders, autonomous dysregulations, and impaired development. Diagnosis depends on quantitative detection of neurotransmitters in cerebrospinal fluid, since peripheral markers in blood or urine are less reliable. Treatment is based on supplementation of the missing neurotransmitter precursors or restoring deficient cofactors for endogenous enzymatic synthesis. In recent years, knowledge about this orphan group of diseases increased substantially among clinicians. However, the difficult task of integrating clinical symptoms and laboratory values still leads to a critical delay in diagnosis and therapy for patients. This review aims at enhancing the understanding of neurotransmitter disorders and should help practicing clinicians to choose useful diagnostic steps on the way to a valid diagnosis.

Heterogeneous clinical spectrum of DNAJC12-deficient hyperphenylalaninemia: from attention deficit to severe dystonia and intellectual disability

BackgroundAutosomal recessive mutations in DNAJC12, encoding a cochaperone of HSP70 with hitherto unknown function, were recently described to lead to hyperphenylalaninemia, central monoamine neurotransmitter (dopamine and serotonin) deficiency, dystonia and intellectual disability in six subjects affected by homozygous variants.ObjectivePatients exhibiting hyperphenylalaninemia in whom deficiencies in hepatic phenylalanine hydroxylase and tetrahydrobiopterin cofactor metabolism had been excluded were subsequently analysed for DNAJC12 variants.MethodsTo analyse DNAJC12, genomic DNA from peripheral blood (Sanger sequencing), as well as quantitative messenger RNA (Real Time Quantitative Polymerase Chain Reaction (RT-qPCR)) and protein expression (Western blot) from primary skin fibroblasts were performed.ResultsWe describe five additional patients from three unrelated families with homozygosity/compound heterozygosity in DNAJC12 with three novel variants: c.85delC/p.Gln29Lysfs*38, c.596G>T/p.*199Leuext*42 and c.214C>T/p.(Arg72*). In contrast to previously reported DNAJC12-deficient patients, all five cases showed a very mild neurological phenotype. In two subjects, cerebrospinal fluid and primary skin fibroblasts were analysed showing similarly low 5-hydroxyindolacetic acid and homovanillic acid concentrations but more reduced expressions of mRNA and DNAJC12 compared with previously described patients. All patients responded to tetrahydrobiopterin challenge by lowering blood phenylalanine levels.ConclusionsDNAJC12 deficiency appears to result in a more heterogeneous neurological phenotype than originally described. While early identification and institution of treatment with tetrahydrobiopterin and neurotransmitter precursors is crucial to ensure optimal neurological outcome in DNAJC12-deficient patients with a severe phenotype, optimal treatment for patients with a milder phenotype remains to be defined.

Heptanoate as a Neural Fuel: Energetic and Neurotransmitter Precursors in Normal and Glucose Transporter I-Deficient (G1D) Brain

It has been postulated that triheptanoin can ameliorate seizures by supplying the tricarboxylic acid cycle with both acetyl-CoA for energy production and propionyl-CoA to replenish cycle intermediates. These potential effects may also be important in other disorders associated with impaired glucose metabolism because glucose supplies, in addition to acetyl-CoA, pyruvate, which fulfills biosynthetic demands via carboxylation. In patients with glucose transporter type I deficiency (G1D), ketogenic diet fat (a source only of acetyl-CoA) reduces seizures, but other symptoms persist, providing the motivation for studying heptanoate metabolism. In this work, metabolism of infused [5,6,7-13C3]heptanoate was examined in the normal mouse brain and in G1D by 13C-nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS). In both groups, plasma glucose was enriched in 13C, confirming gluconeogenesis from heptanoate. Acetyl-CoA and glutamine levels became significantly higher in the brain of G1D mice relative to normal mice. In addition, brain glutamine concentration and 13C enrichment were also greater when compared with glutamate in both animal groups, suggesting that heptanoate and/or C5 ketones are primarily metabolized by glia. These results enlighten the mechanism of heptanoate metabolism in the normal and glucosedeficient brain and encourage further studies to elucidate its potential antiepileptic effects in disorders of energy metabolism.