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Nicotine ingested from smoking exerts neuroprotection and developmental neurotoxicity in central nervous system. It can produce several changes of cognitive behaviors through regulating the release of different neurotransmitters in the brain. However, the effects of nicotine exposure or withdrawal on neurotransmitter metabolism of hippocampus are still unclear. In this study, we real-time evaluated the dynamic alterations in neurotransmitter metabolism of hippocampal neuronal (HT22) cells induced by nicotine exposure and withdrawal at relevant exposure levels of smoking and secondhand smoke by using a microfluidic chip-coupled with liquid chromatography-mass spectrometry (MC-LC-MS) system. We found HT22 cells mainly released related neurotransmitters of tryptophan and choline metabolism, both nicotine exposure and withdraw altered its neurotransmitters and their metabolites release. Exposure to nicotine mainly altered the secretion of serotonin, kynurenic acid, choline and acetylcholine of HT22 cells to improve hippocampal dependent cognition, and the change are closely related to the dose and duration of exposure. Moreover, the altered metabolites could rapidly recover after nicotine withdrawal, but picolinic acid was elevated. MC-LC-MS system used in present study showed a greater advantage to detect unstable metabolites than conventional method by using in vitro model, and the results of dynamic alterations of neurotransmitter metabolism induced by nicotine might provide a potential targets for drug development of neuroprotection or cognitive improvement.

At the time when the number of children with autism spectrum disorders (ASD) is increasing, the number of studies that investigate the clinical features of the disease, pathogenesis, etiological factors and methods of treatment is increasing too. There is no single answer to the questions of etiology and pathogenesis of this disorder for today. In this article, we present modern literature data regarding the problem of neurotransmitter metabolism in children with ASD. Also, the data obtained during the determination of gamma-aminobutyric acid (GABA) concentration in the blood plasma of children with cognitive epileptiform disintegration (n = 45) and children with ASD without epileptic seizures (n = 15) are given. According to the results of the study, there was a decrease in the average concentration of GABA in children with cognitive epileptiform disintegration as compared to the control group (n = 12). There were no significant differences in the mean concentration of GABA between the group of children with ASD without epileptic seizures and the control group (p < 0.001). Our results and a review of literature data allow us to state the necessity of using drugs that regulate the metabolism of neurotransmitters, especially GABA, in the treatment of children with ASD.

Background Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by persistent deficits in social communication and interaction. Common genetic variation appears to play a key role in the development of this condition. In this systematic review, we describe the relationship between genetic variations and autism. We created a gene dataset of the genes involved in the pathogenesis of autism and performed an over-representation analysis to evaluate the biological functions and molecular pathways that may explain the associations between these variants and the development of ASD. Results 177 studies and a gene set composed of 139 were included in this qualitative systematic review. Enriched pathways in the over-representation analysis using the KEGG pathway database were mostly associated with neurotransmitter receptors and their subunits. Major over-represented biological processes were social behavior, vocalization behavior, learning and memory. The enriched cellular component of the proteins encoded by the genes identified in this systematic review were the postsynaptic membrane and the cell junction. Conclusions Among the biological processes that were examined, genes involved in synaptic integrity, neurotransmitter metabolism, and cell adhesion molecules were significantly involved in the development of autism.

Baihe Jizihuang Tang (BHT) is a traditional Chinese medicine (TCM) prescription, which can also be used as a nutritional food with medicinal value. Herein, we aimed to clarify the antidepressive effects and molecular mechanism of BHT. Network pharmacological analysis; chronic unpredictable mild stress (CUMS) rat model assessment; behavioral tests; analysis of hippocampal neurotransmitter levels, hippocampal pathological structure, and hypothalamic-pituitary-adrenal (HPA) axis; western blot analysis; 16s RNA sequencing; ultraperformance liquid chromatography (UPLC)/mass spectrometry (MS); and high-performance liquid chromatography (HPLC)/ultraviolet (UV) analysis were used. We found 8 potentially active components and 12 targets from the database. KEGG analysis suggested that BHT significantly affected BDNF/tyrosine receptor kinase B levels, glutamate binding, synaptic transmission based on neurotransmitter signal, and the response to glucocorticoid signaling pathways. Consistently, 7 chemical components were identified using UPLC/quadrupole time-of-flight/MS; among them, regalosides A, B, C, and E were unique components of lily of TCM, and their content in BHT was significantly different: regaloside A > B > E > C. BHT could nourish hippocampal neurons, affect neurotransmitter metabolism, reduce HPA axis hyperactivity, improve deficits in hippocampal tissue structure, and change depressive behavior. Moreover, BHT regulated BDNF expression in the hippocampus and improved intestinal flora deficits in CUMS rats by changing the content of Bifidobacterium, Rothia, Glutamicibacter, and Lactobacillus at the genus level. Collectively, BHT attenuated CUMS-induced depression-like behavior by regulating BDNF and intestinal flora disorder through the brain-gut axis. Therefore, including BHT in the medication list may constitute a potential strategy for preventing depression.

Infectious diseases may affect brain function and cause encephalopathy even when the pathogen does not directly infect the central nervous system, known as infectious disease-associated encephalopathy. The systemic inflammatory process may result in neuroinflammation, with glial cell activation and increased levels of cytokines, reduced neurotrophic factors, blood–brain barrier dysfunction, neurotransmitter metabolism imbalances, and neurotoxicity, and behavioral and cognitive impairments often occur in the late course. Even though infectious disease-associated encephalopathies may cause devastating neurologic and cognitive deficits, the concept of infectious disease-associated encephalopathies is still under-investigated; knowledge of the underlying mechanisms, which may be distinct from those of encephalopathies of non-infectious cause, is still limited. In this review, we focus on the pathophysiology of encephalopathies associated with peripheral (sepsis, malaria, influenza, and COVID-19), emerging therapeutic strategies, and the role of neuroinflammation. Graphic abstract

Exposure to acute versus chronic stressors and threats activates the immune system in adaptive and maladaptive manners, respectively. While acute activation of the immune system in response to threat is homeostatically regulated by glucocorticoid negative feedback, chronic activation of the immune system arising from persistent stress exposure can contribute to an allostatic load with an inflammatory diathesis that has been implicated in stress-related psychopathology, including of depression and anxiety. Increased inflammation in the periphery and in the brain arising from chronic stress exposure can alter neurotransmitter metabolism and impact activation of brain regions to increase adverse behavioral health symptoms (e.g. anhedonia, anxiety, fatigue) and emotion dysregulation. While interventions targeting the immune system and its downstream effects on the brain for the treatment of depression and other psychiatric disorders has been of great interest as they have shown some efficacy in treating stress-related behavioral health disorders, future studies are necessary to better characterize the contexts under which anti-inflammatory agents should be used to treat stress-related psychopathology.

Bio-neuronal led psychiatric abnormalities transpired by the loss of neuronal structure and function (neurodegeneration), pro-inflammatory cytokines, microglial dysfunction, altered neurotransmission, toxicants, serotonin deficiency, kynurenine pathway, and excessively produced neurotoxic substances. These uncontrolled happenings in the etiology of psychiatric disorders initiate further changes in neurotransmitter metabolism, pathologic microglial, cell activation, and impaired neuroplasticity. Inflammatory cytokines, the outcome of dysfunctional mitochondria, dysregulation of the immune system, and under stress functions of the brain are leading biochemical factors for depression and anxiety. Nanoscale drug delivery platforms, inexpensive diagnostics using nanomaterials, nano-scale imaging technologies, and ligand-conjugated nanocrystals used for elucidating the molecular mechanisms and foremost cellular communications liable for such disorders are highly capable features to study for efficient diagnosis and therapy of the mental illness. These theranostic tools made up of multifunctional nanomaterials have the potential for effective and accurate diagnosis, imaging of psychiatric disorders, and are at the forefront of leading technologies in nanotheranostics openings field as they can collectively and efficiently target the stimulated territories of the cerebellum (cells and tissues) through molecular-scale interactions with higher bioavailability, and bio-accessibility. Specifically, the nanoplatforms based neurological changes are playing a significant role in the diagnosis of psychiatric disorders and portraying the routes of functional restoration of mental disorders by newer imaging tools at nano-level in all directions. Because of these nanotherapeutic platforms, the molecules of nanomedicine can penetrate the Blood-Brain Barrier with an increased half-life of drug molecules. The discoveries in nanotheranostics and nanotherapeutics inbuilt unique multi-functionalities are providing the best multiplicities of novel nanotherapeutic potentialities with no toxicity concerns at the level of nano range.

Introduction. Despite the apparent connection of the existing neurological disorders and changes in the psycho-emotional sphere with sleep disorders in patients with chronic mercury intoxication (CRI), these relationships remain the least studied in the clinic neurointoxications. The study aimed to establish a connection between neurophysiological, biochemical, and psychopathological indicators in patients with occupational chronic mercury intoxication and insomnia. Materials and methods. Thirty-six patients took part in the examination in the remote period of CRI. The average age of patients in this group was 50.7±1.05 years, with an average work experience of 14.7±1.05. The authors carried out a psychological examination to determine the levels of depression, anxiety, asthenic state, computed electroencephalography (EEG), cognitive evoked potentials (CEP), polysomnography, the level of neurotransmitters. Results. The study showed that asthenization, when exposed to mercury, occurs due to a decrease in the limbic-hypothalamo-reticular complex activity (the presence of equivalent dipole sources of pathological activity in the area of diencephalic formations (thalamus, hypothalamus) in 56.2±5.6% of cases. The study showed a decrease in activity cerebral cortex, confirmed by weakening the coherent connections of the α-range in the occipital, central and frontal leads according to the data of coherent EEG analysis and changes on the part of the CEP. There was a direct correlation between the level of total sleep time and the serotonin level (rs=0.45), an inverse relationship between the level of depression and histamine level (rs=-0.56). Conclusion. The studies carried out to make it possible to establish the mechanisms of insomnia disorders in chronic mercury intoxication, which cause a weakening of the tone of the cerebral cortex and changes in neurotransmitter metabolism, as well as disorders of the reticular system with limbic structures. The study showed a close direct relationship between neurophysiological, psychological, and biochemical parameters in implementing insomnia in patients with chronic mercury intoxication.

Astrocytes are a heterogeneous population of neural cells with diverse structural, functional and molecular characteristics responsible for homeostasis and protection of the central nervous system (CNS). Unlike neurones, astrocytes do not generate action potentials, but employ fluctuations of cytosolic ions as a substrate for their excitability. Ionic signals are associated with neuronal activity and these signals initiate an array of responses ranging from the activation of plasmalemmal homeostatic transporters to the secretion of numerous signalling molecules including neuromodulators, neurotransmitter precursors, metabolic substrates, trophic factors and cytokines. Thus, astrocytes regulate the synaptic connectivity of the neuronal networks by supporting neurotransmitter metabolism, synaptogenesis, synaptic elimination and the synaptic plasticity that contributes to cognitive processing including learning, memory, emotionality and behaviour. Astroglia-specific regulatory pathways affect the most fundamental properties of neuronal networks from their excitability to synaptic connectivity. Thus, it is the concerted action of glia and neurones, which, through distinct mechanisms, produce the behavioural outputs of the ultimate control centre that we call the brain.

Цель исследования - сравнительный анализ содержания про- и противовоспалительных цитокинов и аутоантител к нейромедиаторам дофамину, норадреналину, серотонину, глутамату и ГАМК в сыворотке крови пациенток с алкогольной зависимостью и депрессией разной степени тяжести. Методика. Клиническое обследование и создание банка биологического материала выполнены на базе отделений аффективных расстройств и аддиктивных состояний и лаборатории клинической психонейроиммунологии и нейробиологии НИИ психического здоровья Томского НИМЦ РАН. Исследована сыворотка крови 52 женщин в возрасте 40-55 лет: 17 условно здоровых лиц, и 35 пациенток с аффективными и аддиктивными расстройствами. В соответствии с МКБ-10 у 6 пациенток диагностирован синдром зависимости от алкоголя (F10.2). У 29 пациенток диагностирована депрессия разной степени тяжести. В подгруппу легкой депрессии (сумма баллов по шкале Гамильтона HDRS до 16 баллов включительно) вошли 13 пациенток: 5 с депрессивным эпизодом легкой степени F32.0 и 8 с дистимией F34.1. В подгруппу умеренной депрессии (сумма баллов по шкале Гамильтона выше 16 баллов) вошли 16 пациенток: 7 с депрессивным эпизодом средней степени F32.1 и 9 с рекуррентной депрессией F33.1. Антитела к нейромедиаторам дофамину, норадреналину, серотонину, глутамату и ГАМК в сыворотке крови определяли методом твердофазного иммуноферментного анализа на полистироловых планшетах, активированных соответствующими тест-антигенами. Интерлейкины в сыворотке крови определяли методом иммуноферментного анализа с использованием тест-систем производства ООО Цитокин (Санкт-Петербург). Определяли баланс провоспалительных цитокинов - интерлейкинов (ИЛ 1β, ИЛ 6) и противовоспалительных - ИЛ 10. Результаты. Уровень аутоантител к нейромедиаторам связан с тяжестью депрессии. При легкой депрессии отличия от контрольного уровня незначительны. При умеренной депрессии повышен уровень антител к серотонину, глутамату и ГАМК. Спектр антител при алкоголизме сходен с таковым при умеренной депрессии. Можно предполагать, что данные паттерны отражают коморбидное течение депрессии и аддикции. Соотношение содержания провоспалительного (ИЛ 6) и противовоспалительного (ИЛ 10) цитокинов в сыворотке крови при алкоголизме незначительно отличалось от контрольного уровня, в то время как при отягощении депрессии это соотношение существенно повышалось и у 20% обследованных в явной форме указывало на преобладание воспаления над компенсаторными процессами. Заключение. Феномен нейровоспаления не является достаточным для понимания нейроиммунных механизмов коморбидной патологии. Иммунорегуляция нейромедиаторного обмена является новым источником информации о нейроиммунном дисбалансе при сочетанных расстройствах. Aim. Comparative analysis of concentrations of pro- and anti-inflammatory cytokines and autoantibodies to the neurotransmitters dopamine, norepinephrine, 5-hydroxytryptamine, glutamate, and GABA in the blood serum of female patients with alcohol dependence and depression of different severity. Methods. Clinical examination and creation of a bank of biological material were performed at the Departments of Affective Disorders and Addictive Conditions and the Laboratory of Clinical Psychoneuroimmunology and Neurobiology of the Mental Health Institute, Tomsk Scientific Research Center of the Russian Academy of Sciences. Blood serum of 52 women aged 40-55 years was studied, including 17 conditionally healthy individuals, and 35 patients with affective and addictive disorders. In accordance with ICD-10, 6 patients were diagnosed with alcohol dependence syndrome (F10.2), and 29 patients were diagnosed with depression of different severity. The subgroup of mild depression with a Hamilton Depression Rating Scale (HDRS) score 16 included 16 patients (7 with a moderate depressive episode F32.1 and 9 with recurrent depression F33.1). Serum antibodies to the neurotransmitters dopamine (DA), norepinephrine (NA), 5-hydroxytryptamine (5-HT), glutamate (GLU), and GABA were determined by enzyme-linked immunosorbent assay (ELISA) on polystyrene plates activated with the respective test antigens. Serum interleukins (IL) were measured using ELISA test systems. The balance of pro-inflammatory (IL 1β and IL 6) and anti-inflammatory (IL 10) cytokines was determined. Statistical analysis was performed with the φ Fisher criteria, and data were graphically presented as mean values. Results. Concentrations of autoantibodies to neurotransmitters were related with the severity of depression. In mild depression, differences from the control values were negligible. In moderate depression, levels of antibodies to 5-hydroxytryptamine, glutamate, and GABA were increased. In alcohol dependence, the array of antibodies was similar to that in moderate depression. These patterns apparently reflect the comorbid course of depression and addiction. The ratio of pro-inflammatory (IL 6) to anti-inflammatory (IL 10) cytokine serum concentrations in alcohol dependence was slightly different from the control ratio. At the same time in more severe depression, this ratio significantly increased and clearly indicated prevalence of inflammation over compensatory processes in 20% of the patients. Conclusion. The phenomenon of neuroinflammation is not sufficient to understand neuroimmune mechanisms of the comorbid pathology. Immunoregulation of neurotransmitter metabolism is a new source of information about neuroimmune imbalance in combined disorders.

Objective: to investigate the effect of citicoline (CTC) on gene transcription.Material and methods. Chemotranscriptome analysis of the CTC molecule was carried out on an NPC.TAK model, provided that the cells were incubated with CTC for 24 hours.Results and discussion. CTC dose-dependently affected the transcription of 8,838 out of 12,716 annotated human genes, mainly by increasing the transcription of the genes involved: 1) in the neurotransmitter metabolism of serotonin (n=36), dopamine (n=32), GABA (n=14), and acetylcholine (n=27); 2) in showing the effects of neurotrophic factors (n=152), including nerve growth factor (n=11); 3) in maintaining the cardiovascular system (vasodilation and cardiac electrical activity; a total of 76 genes). CTC reduced the transcription of the genes, whose protein activity supported inflammation (n=86) and cell division (n=656). CTC elevated the expression of 60 genes involved in triglyceride processing and decreased the expression of 51 genes whose proteins were involved in cholesterol metabolism. CTC increased the transcription of the genes involved in the body’s response to various drugs, including antiepileptic drugs (n=20), dopaminergic agents (n=19), antipsychotics (n=38), anxiolytics (n=21), sedatives (n=22), antidepressants (n=35), anesthetics (n=23), and antidementia drugs (n=11).Conclusion. Chemotranscriptome analysis indicated the positive effect of CTC on neurotransmission, neuroprotection, lipid profile, and a higher neuronal susceptibility to other neuroactive drugs.

Synaptic transmission is closely linked to brain energy and neurotransmitter metabolism. However, the extent of brain metabolism of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), and the relative metabolic contributions of neurons and astrocytes, are yet unknown. The present study was designed to investigate the functional significance of brain GABA metabolism using isolated mouse cerebral cortical slices and slices of neurosurgically resected neocortical human tissue of the temporal lobe. By using dynamic isotope labeling, with [15 N]GABA and [U-13 C]GABA as metabolic substrates, we show that both mouse and human brain slices exhibit a large capacity for GABA metabolism. Both the nitrogen and the carbon backbone of GABA strongly support glutamine synthesis, particularly in the human cerebral cortex, indicative of active astrocytic GABA metabolism. This was further substantiated by pharmacological inhibition of the primary astrocytic GABA transporter subtype 3 (GAT3), by (S)-SNAP-5114 or 1-benzyl-5-chloro-2,3-dihydro-1H-indole-2,3-dione (compound 34), leading to significant reductions in oxidative GABA carbon metabolism. Interestingly, this was not the case when tiagabine was used to specifically inhibit GAT1, which is predominantly found on neurons. Finally, we show that acute GABA exposure does not directly stimulate glycolytic activity nor oxidative metabolism in cultured astrocytes, but can be used as an additional substrate to enhance uncoupled respiration. These results clearly show that GABA is actively metabolized in astrocytes, particularly for the synthesis of glutamine, and challenge the current view that synaptic GABA homeostasis is maintained primarily by presynaptic recycling.

Pyridoxal 5′‐phosphate (PLP) is an essential cofactor for neurotransmitter metabolism. Pyridoxal phosphatase (PDXP) deficiency in mice increases PLP and γ‐aminobutyric acid levels in the brain, yet how PDXP is regulated is unclear. Here, we identify the Ca\(^{2+}\)‐ and integrin‐binding protein 1 (CIB1) as a PDXP interactor by yeast two‐hybrid screening and find a calmodulin (CaM)‐binding motif that overlaps with the PDXP‐CIB1 interaction site. Pulldown and crosslinking assays with purified proteins demonstrate that PDXP directly binds to CIB1 or CaM. CIB1 or CaM does not alter PDXP phosphatase activity. However, elevated Ca\(^{2+}\) concentrations promote CaM binding and, thereby, diminish CIB1 binding to PDXP, as both interactors bind in a mutually exclusive way. Hence, the PDXP‐CIB1 complex may functionally differ from the PDXP‐Ca\(^{2+}\)‐CaM complex.

Accumulating evidence suggests that neuroinflammation plays an important role in etiology of psychiatric disorders. Neuronflammation involves a combination of psychological, neuroendocrine, and nervous systems resulting in changes of neurotransmitter metabolism, dysregulation of the hypothalamus-pituitary-adrenal axis, pathologic microglial cell activation, impaired neuroplasticity, and structural and functional brain changes affecting cognition and emotional behavior. Inflammatory cytokines have been postulated to be the possible link and culprit in the disruption of these systems. The outcome of any type of dysregulation of the immune system in the brain might lead to occurrence of depression, anxiety. This review focuses on the possible impact of dysregulated cytokine networks which may cause pathogenesis of affective disorders such as depression and anxiety.

Objective The aim: A correction of cholinergic insufficiency for the treatment of cognitive impairment in chronic brain ischemia. Patients and methods Materials and methods: In the period 2014 - 2017, 88 people aged 40 to 68 years were comprehensively examined in dynamics. Patients were divided into three groups, statistically comparable to the main disease - CCI 2 degrees, gender and age. In addition to the protocol, patients with discirculatory encephalopathy of all the investigated groups received a complex of drugs aimed at correcting neurotransmitter metabolism. Results Results: The statistically significant manifestations of the recovery of cognitive function (according to the MMSE scale) after the application of the developed complex therapy were associated mainly with a decrease in impulsivity due to an increase in the level of attention. The statistically significant manifestations of a decrease in the level of anxietydepressive disorders (according to the DASS-21 scale) after the application of the developed complex therapy were associated mainly with a decrease in anxiety due to the restoration of neurohumoral balance. Conclusion Conclusions: The inclusion in the treatment protocol for CCI complex of drugs aimed at eliminating cholinergic deficiency, acetylcholinesterase inhibitors in combination with choline precursors, leads to the correction of cognitive impairment in chronic brain ischemia.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (, Dietmar Hopp Stiftung (DE); Medical Faculty of the University of Heidelberg.

PICALM and CLU genes have been linked to alterations in brain biochemical processes that may have an impact on Alzheimer’s disease (AD) development and neurophysiological dynamics. The aim of this study is to analyze the relationship between the electroencephalographic (EEG) activity and the PICALM and CLU alleles described as conferring risk or protective effects on AD patients and healthy controls. For this purpose, EEG activity was acquired from: 18 AD patients and 12 controls carrying risk alleles of both PICALM and CLU genes, and 35 AD patients and 12 controls carrying both protective alleles. Relative power (RP) in the conventional EEG frequency bands (delta, theta, alpha, beta, and gamma) was computed to quantify the brain activity at source level. In addition, spatial entropy (SE) was calculated in each band to characterize the regional distribution of the RP values throughout the brain. Statistically significant differences in global RP and SE at beta band (p-values < 0.05, Mann–Whitney U-test) were found between genotypes in the AD group. Furthermore, RP showed statistically significant differences in 58 cortical regions out of the 68 analyzed in AD. No statistically significant differences were found in the control group at any frequency band. Our results suggest that PICALM and CLU AD-inducing genotypes are involved in physiological processes related to disruption in beta power, which may be associated with physiological disturbances such as alterations in beta-amyloid and neurotransmitter metabolism.

Iron is essential for the functioning of all cells and organs, most critically for the developing brain in the fundamental neuronal processes of myelination, energy and neurotransmitter metabolism. Iron deficiency, especially in the first 1000 days of life, can result in long-lasting, irreversible deficits in cognition, motor function and behaviour. Pregnant women, infants and young children are most vulnerable to iron deficiency, due to their high requirements to support growth and development, coupled with a frequently inadequate dietary supply. An unrecognised problem is that even if iron intake is adequate, common pregnancy-related and lifestyle factors can affect maternal–fetal iron supply in utero, resulting in an increased risk of deficiency for the mother and her fetus. Although preterm birth, gestational diabetes mellitus and intrauterine growth restriction are known risk factors, more recent evidence suggests that maternal obesity and delivery by caesarean section further increase the risk of iron deficiency in the newborn infant, which can persist into early childhood. Despite the considerable threat that early-life iron deficiency poses to long-term neurological development, life chances and a country's overall social and economic progress, strategies to tackle the issue are non-existent, too limited or totally inappropriate. Prevention strategies, focused on improving the health and nutritional status of women of reproductive age are required. Delayed cord clamping should be considered a priority. Better screening strategies to enable the early detection of iron deficiency during pregnancy and early-life should be prioritised, with intervention strategies to protect maternal health and the developing brain.

Dystonia is a complex neurological movement disorder characterized by involuntary muscle contractions. Increasing studies implicate the microbiome as a possible key susceptibility factor for neurological disorders, but the relationship between the gut microbiota and dystonia remains poorly explored. Here, the gut microbiota of 57 patients with isolated dystonia and 27 age- and environment-matched healthy controls was analyzed by 16S rRNA gene amplicon sequencing. Further, integrative analysis of the gut microbiome and serum metabolome measured by high-performance liquid chromatography-mass spectrometry was performed. No difference in α-diversity was found, while β-diversity was significantly different, with a more heterogeneous community structure among dystonia patients than among controls. The most significant changes in dystonia highlighted an increase in Clostridiales, including Blautia obeum, Dorea longicatena, and Eubacterium hallii, and a reduction in Bacteroides vulgatus and Bacteroides plebeius. The functional analysis revealed that genes related to tryptophan and purine biosynthesis were more abundant in gut microbiota from patients with dystonia, while genes linked to citrate cycle, vitamin B6, and glycan metabolism were less abundant. The evaluation of serum metabolites revealed altered levels of l-glutamic acid, taurine, and d-tyrosine, suggesting changes in neurotransmitter metabolism. The most modified metabolites strongly inversely correlated with the abundance of members belonging to the Clostridiales, revealing the effect of the gut microbiota on neurometabolic activity. This study is the first to reveal gut microbial dysbiosis in patients with isolated dystonia and identified potential links between gut microbiota and serum neurotransmitters, providing new insight into the pathogenesis of isolated dystonia. IMPORTANCE Dystonia is the third most common movement disorder after essential tremor and Parkinson’s disease. However, the cause for the majority of cases is not known. This is the first study so far that reveals significant alterations of gut microbiome and correlates the alteration of serum metabolites with gut dysbiosis in patients with isolated dystonia. We demonstrated a general overrepresentation of Clostridiales and underrepresentation of Bacteroidetes in patients with dystonia in comparison with healthy controls. The functional analysis found that genes related to the biosynthesis of tryptophan, which is the precursor of the neurotransmitter serotonin, were more active in isolated dystonia patients. Altered levels of several serum metabolites were found to be associated with microbial changes, such as d-tyrosine, taurine, and glutamate, indicating differences in neurotransmitter metabolism in isolated dystonia. Integrative analysis suggests that neurotransmitter system dysfunction may be a possible pathway by which the gut microbiome participates in the development of dystonia. The gut microbiome changes provide new insight into the pathogenesis of dystonia, suggesting new potential therapeutic directions.

The establishment of endometrial receptivity is a prerequisite for successful pregnancy. Women with adenomyosis possess a lower chance of clinical pregnancy after assisted reproductive technology, which is partially due to impaired endometrial receptivity. The establishment of endometrial receptivity requires the participation of multiple processes, and proper endometrial epithelial cell (EEC) proliferation is indispensable. Monoamine oxidase A (MAOA) is a key molecule that regulates neurotransmitter metabolism in the nervous system. In the present study, we demonstrated a novel role for MAOA in the establishment of endometrial receptivity in women with adenomyosis and in an adenomyotic mouse model. Attenuated MAOA impairs endometrial receptivity by promoting inappropriate proliferation of EECs via the downregulation of FOXO1 during the window of implantation. These results revealed that MAOA plays a vital role in endometrial receptivity in female reproduction.

The asymmetric localization of planar cell polarity (PCP) proteins is essential for the establishment of many planar polarized cellular processes, but the mechanisms that maintain these asymmetric distributions remain poorly understood. A body of evidence has tied oriented subapical microtubules (MTs) to the establishment of PCP protein polarity, yet recent studies have suggested that the MT cytoskeleton is later dispensable for the maintenance of this asymmetry. As MTs underlie the vesicular trafficking of membrane-bound proteins within cells, the requirement for MTs in the maintenance of PCP merited further investigation. We investigated the complex interactions between PCP proteins and the MT cytoskeleton in the polarized context of the floorplate of the zebrafish neural tube. We demonstrated that the progressive posterior polarization of the primary cilia of floorplate cells requires not only Vangl2 but also Fzd3a. We determined that GFP-Vangl2 asymmetrically localizes to anterior membranes whereas Fzd3a-GFP does not polarize on anterior or posterior membranes but maintains a cytosolic enrichment at the base of the primary cilium. Vesicular Fzd3a-GFP is rapidly trafficked along MTs primarily toward the apical membrane during a period of PCP maintenance, whereas vesicular GFP-Vangl2 is less frequently observed. Nocodazole-induced loss of MT polymerization disrupts basal body positioning as well as GFP-Vangl2 localization and reduces cytosolic Fzd3a-GFP movements. Removal of nocodazole after MT disruption restores MT polymerization but does not restore basal body polarity. Interestingly, GFP-Vangl2 repolarizes to anterior membranes and vesicular Fzd3a-GFP dynamics recover after multiple hours of recovery, even in the context of unpolarized basal bodies. Together our findings challenge previous work by revealing an ongoing role for MT-dependent transport of PCP proteins in maintaining both cellular and PCP protein asymmetry during development.

Background Patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) frequently show depressive symptoms clinically and increasing evidence indicates a correlation between CP/CPPS and depression. However, the underlying mechanisms of CP/CPPS-related depression remain poorly understood. Here, we sought to determine the role of hippocampal microglial activation and neurobiological changes in a mouse model of experimental autoimmune prostatitis (EAP)-induced depression and the treatment efficacy of Chinese herb extract baicalein. Methods EAP was induced through intradermal injection of prostate antigen and adjuvant twice. Then, mice were assessed for affective behaviors in the open field test, elevated plus maze, forced swim test, and tail suspension test. The morphology and function of microglia and astrocytes were detected by immunofluorescence, Western blotting, and transmission electron microscopy. Proinflammatory mediators along with serotonin transporter (SLC6A4/SERT) and indoleamine 2,3-dioxygenase (IDO) were quantified with reverse transcription-polymerase chain reaction (RT‑PCR), and serum serotonin concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Proton magnetic resonance spectroscopy (1H-MRS) was performed to measure hippocampal glutamate levels. In addition, baicalein was used in a subset of EAP mice to test its anti-depressant action. Results EAP was successfully established and induced depressive- and anxiety-like behavior in mice. Increasing levels of co-expressed ionized calcium-binding adapter molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) and ultrastructural observations suggested microglial activation and reactive astrocytosis in the hippocampus. These activated microglia resulted in increased expressions of multiple proinflammatory cytokines. Simultaneously, EAP mice showed higher gene expressions of SLC6A4 and IDO and lower concentrations of serotonin. 1H-MRS indicated a decrease in the glutamate + glutamine (Glx)/total creatine (tCr) ratio in EAP mice. Furthermore, baicalein treatment alleviated the depressive-like behavior and neuroinflammation by suppressing the nuclear factor-kappa B (NF-κB) pathway. Conclusion Our data indicate that EAP-induced depressive-like behavior is linked to microglia activation and subsequent neurotransmitter metabolism. Moreover, baicalein attenuates behavioral changes by inhibiting neuroinflammation via downregulation of the NF-κB pathway.

Background: Post-stroke depression (PSD) is a frequent and serious complication of stroke. However, the underlying molecular basis of PSD remains largely unknown, and no empirical laboratory tests were available to diagnose this disorder. Materials and methods: A proton nuclear magnetic resonance (1H NMR)-based metabonomic approach was employed to profile plasma samples from 32 PSD, 35 stroke patients and 35 healthy comparison subjects (the training set) in order to identify metabolite biomarkers for PSD. Then, 10 PSD, 11 stroke patients and 11 healthy comparison subjects (test set) were used to validate the diagnostic performance of these biomarkers. Results: The multivariate statistical analysis demonstrated that PSD group was significantly distinguishable from non-PSD groups (non-depression stroke patients and healthy comparison group). Five plasma metabolites (phenylalanine, tyrosine, 1-methylhistidine, 3-methylhistidine and LDL CH3-(CH2)n-) were identified responsible for distinguishing PSD from non-PSD subjects. These metabolites were mainly involved in neurotransmitter metabolism and oxidative stress. The biomarker panel composing of these metabolites was capable of distinguishing test samples with a sensitivity of 100.0% and a specificity of 95.5%. Conclusion: Our findings suggest that plasma disturbances of neurotransmitter levels and oxidative stress were implicated in the onset of PSD; these disturbed metabolites biomarkers facilitate to the development of diagnostic tool for PSD.

In this study, the polyphenols content, α‐amylase, α‐glucosidase and cholinesterase‐inhibiting activities of cloudy peach (Prunus persica) juices, were measured immediately after thermal treatment and after storage (6 months at 4 and 30 °C). The study showed that some cultivars were more useable for industry than others. Due to the high content of polyphenols and a high ability to inhibit enzymes linked to type 2 diabetes and Alzheimer's disease, noteworthy are the juices obtained from ‘Redheaven early’ and ‘Redheaven’ cultivars. The content of total phenolics ranged from 1109.7 to 390.7 mg/L of juice, and the dominant fraction was polymeric procyanidins. Following 6 months of storage a significant change was observed in the content of polyphenols, especially flavonols and anthocyanins. The data compiled from the conducted study indicate that peach juice could be useful for the juice industry as a promising source of bioactive compounds.

Chronic intranasal administration of antibodies to glutamate to aging C57Bl/6 mice improved passive avoidance conditioning, had no effect on horizontal and vertical locomotor activity, but slowed locomotion in the open-field test. Administration of antibodies to glutamate increased the content of dopamine and its metabolites in mouse hippocampus, but had no effect on the metabolism of neurotransmitter amino acids. In the frontal cortex, antibodies to glutamate did not affect neurotransmitter metabolism, but increased the level of both excitatory and inhibitory amino acids without changing their ratio.

Essential hypertension (EH) is a prevalent chronic medical condition and a major risk factor for cardiovascular morbidity and mortality. Neurotransmitters are involved in the physiological process of blood pressure regulation in the body. Studies have shown that oleanolic acid (OA) can effectively regulate neurotransmitter-related metabolic disorders caused by EH, but the mechanism is still unclear. Here, we studied the neurotransmitter metabolic profiles in five brain regions by targeted metabolomics approaches in spontaneously hypertensive rats (SHRs) treated with OA and vehicle. Samples from five brain regions (hippocampus, striatum, hypothalamus, temporal lobe, and frontal lobe) were collected from the control group, the spontaneously hypertensive rat (SHR) group, and the OA group. Targeted metabolomics based on UPLC-Q-Exactive-MS was employed to characterize the dramatically changed neurotransmitters in the brain regions of SHRs treated with OA and vehicle. The expressions of the key enzymes involved in the neurotransmitter metabolism were detected by the reverse transcription-polymerase chain reaction (RT-PCR). The metabolomic profiles of SHRs pre-protected by OA were significantly different from those of unprotected SHRs. A total of 18 neurotransmitters could be confirmed as significantly altered metabolites, which were involved in tyrosine and glutamate metabolism as well as other pathways. The results showing seven key enzymes in neurotransmitter metabolism further validated the changes in the metabolic pathways. OA could effectively restore tyrosine metabolism in the striatum and hypothalamus, glutamate metabolism in the hippocampus, striatum and temporal lobe, cholinergic metabolism in the striatum, and histidine metabolism in the hypothalamus due to its inhibition of inflammatory reactions, structural damage of the neuronal cells, and increase in sedative activity. This study indicated that brain region-targeted metabolomics can provide a powerful tool to further investigate the possible mechanism of OA in EH.

Application of advances in nanomedicine and materials science to medical diagnostics is a promising area of research. Surface-enhanced Raman spectroscopy (SERS) is an innovative analytical method that exploits noble metal nanoparticles to noninvasively study cells, cell organelles and protein molecules. Below, we summarize the literature on the methods for early clinical diagnosis of some neurodegenerative and neuroendocrine diseases. We discuss the specifics, advantages and limitations of different diagnostic techniques based on the use of low- and high molecular weight biomarkers. We talk about the prospects of optical methods for rapid diagnosis of neurotransmitter metabolism disorders. Special attention is paid to new approaches to devising optical systems that expand the analytical potential of SERS, the tool that demonstrates remarkable sensitivity, selectivity and reproducibility of the results in determining target analytes in complex biological matrices.

Accumulating evidence has shown that inflammation, the gut microbiota and neurotransmitters are closely associated with the pathophysiology of depression. However, the links between the gut microbiota and neurotransmitter metabolism remain poorly understood. The present study aimed to investigate the neuroinflammatory reactions in chronic restraint stress (CRS)-induced depression and to delineate the potential links between the gut microbiota and neurotransmitter metabolism. C57BL/6 mice were subjected to chronic restraint stress for 5 weeks, followed by behavioural tests (the sucrose preference test, forced swim test, open field test and elevated plus maze) and analysis. The results showed that CRS significantly increased IL-1β, IL-2, IL-6 and TNFα levels and decreased BDNF expression, accompanied by the activation of IκBα-p-NF-κB signalling in the mouse hippocampus. In addition, the neurotransmitter metabolomics results showed that CRS resulted in decreased levels of plasma 5-HT, DA, and NE and their corresponding metabolites, and gut microbiota fecal metabolites with the 16S rRNA gene sequencing indicated that CRS caused marked microbiota dysbiosis in mice, with a significant increase in Helicobacter, Lactobacillus, and Oscillibacter and a decrease in Parabacteroides, Ruminococcus, and Prevotella. Notably, CRS-induced depressive behaviours and the disturbance of neurotransmitter metabolism and microbiota dysbiosis can be substantially restored by dexamethasone (DXMS) administration. Furthermore, a Pearson heatmap focusing on correlations between the microbiota, behaviours and neurotransmitters showed that Helicobacter, Lactobacillus, and Oscillibacter were positively correlated with depressive behaviours but were negatively correlated with neurotransmitter metabolism, and Parabacteroides and Ruminococcus were negatively correlated with depressive behaviours but were positively correlated with neurotransmitter metabolism. Taken together, the results suggest that inflammation is involved in microbiota dysbiosis and the disturbance of neurotransmitter metabolism in CRS-induced depressive changes, and the delineation of the potential links between the microbiota and neurotransmitter metabolism will provide novel strategies for depression treatment.

Understanding of the immediate mechanisms of Mn-induced neurotoxicity is rapidly evolving. We seek to provide a summary of recent findings in the field, with an emphasis to clarify existing gaps and future research directions. We provide, here, a brief review of pertinent discoveries related to Mn-induced neurotoxicity research from the last five years. Significant progress was achieved in understanding the role of Mn transporters, such as SLC39A14, SLC39A8, and SLC30A10, in the regulation of systemic and brain manganese handling. Genetic analysis identified multiple metabolic pathways that could be considered as Mn neurotoxicity targets, including oxidative stress, endoplasmic reticulum stress, apoptosis, neuroinflammation, cell signaling pathways, and interference with neurotransmitter metabolism, to name a few. Recent findings have also demonstrated the impact of Mn exposure on transcriptional regulation of these pathways. There is a significant role of autophagy as a protective mechanism against cytotoxic Mn neurotoxicity, yet also a role for Mn to induce autophagic flux itself and autophagic dysfunction under conditions of decreased Mn bioavailability. This ambivalent role may be at the crossroad of mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis. Yet very recent evidence suggests Mn can have toxic impacts below the no observed adverse effect of Mn-induced mitochondrial dysfunction. The impact of Mn exposure on supramolecular complexes SNARE and NLRP3 inflammasome greatly contributes to Mn-induced synaptic dysfunction and neuroinflammation, respectively. The aforementioned effects might be at least partially mediated by the impact of Mn on α-synuclein accumulation. In addition to Mn-induced synaptic dysfunction, impaired neurotransmission is shown to be mediated by the effects of Mn on neurotransmitter systems and their complex interplay. Although multiple novel mechanisms have been highlighted, additional studies are required to identify the critical targets of Mn-induced neurotoxicity.

Trace levels of oxytetracycline (OTC)-a veterinary antibiotic and feed additive-are widespread in the environment. Studies revealed that OTC potentially impairs thyroid function, which may affect neurobehaviour; however, the impact of exposure to environmental concentrations of OTC on adult neurobehaviour is unknown. In this study, the effects of OTC on zebrafish after 30-day exposure were investigated. The total swimming distance was significantly increased under vibration and light/dark stimulation, while time spent in the white area was prolonged during the black/white preference test, indicating that the zebrafish became bolder and more impulsive under low OTC exposure. Additionally, monoamine neurotransmitter (5-hydroxytryptamine, dopamine, norepinephrine) levels were decreased and gene expression of monoamine oxidase (mao) involved in neurotransmitter metabolism was upregulated at the transcription level after OTC exposure. Because triiodothyronine (T3) levels were enhanced following exposure to OTC, we speculated that T3 may mediate OTC damage to the nervous system. Our simulated molecular docking analysis showed that OTC combined with the sodium iodide cotransporter protein may result in excessive T3 synthesis. We further exposed zebrafish to T3, and they exhibited similar behaviour to the OTC exposure group. In conclusion, environmental OTC may activate monoamine oxidase and enhance the metabolism of monoaminergic neurotransmitters via T3, thereby inducing abnormal neurobehaviour.

Proprioceptive feedback mainly derives from groups Ia and II muscle spindle (MS) afferents and group Ib Golgi tendon organ (GTO) afferents, but the molecular correlates of these three afferent subtypes remain unknown. We performed single cell RNA sequencing of genetically identified adult proprioceptors and uncovered five molecularly distinct neuronal clusters. Validation of cluster-specific transcripts in dorsal root ganglia and skeletal muscle demonstrates that two of these clusters correspond to group Ia MS afferents and group Ib GTO afferent proprioceptors, respectively, and suggest that the remaining clusters could represent group II MS afferents. Lineage analysis between proprioceptor transcriptomes at different developmental stages provides evidence that proprioceptor subtype identities emerge late in development. Together, our data provide comprehensive molecular signatures for groups Ia and II MS afferents and group Ib GTO afferents, enabling genetic interrogation of the role of individual proprioceptor subtypes in regulating motor output., Coordinated movement critically depends on sensory feedback from muscle spindles (MSs) and Golgi tendon organs (GTOs) but the afferents supplying this proprioceptive feedback have remained genetically inseparable. Here the authors use single cell transcriptome analysis to reveal the molecular basis of MS (groups Ia and II) and GTO (group Ib) afferent identities in the mouse.

Background: The microbiota-gut-brain axis is the complex interaction between human gastrointestinal tract flora and the central nervous system. Dysbiosis affects the biochemical signal transduction cascades that modulate neurotransmitter metabolism. Many commonly prescribed medications, such as acid suppressants and antibiotics, cause significant alterations in the human gut microbiome. In vivo animal models and human database studies suggest that gut microbiome disruptions are a clinically significant risk factor for developing mental disorders. Our objective was to investigate the association of proton pump inhibitor (PPI), histamine-2 receptor antagonist (H2RA), and antibiotic prescriptions in the first two years of life with future prescriptions for psychotropic medications. Methods: We conducted a retrospective cohort study of infants born …

Aluminum (Al) is considered as the most abundant metal in the Earth’s crust, being the third most abundant chemical element after oxygen and silicon. Intensive development of the Al industry (Brough and Jouhara, 2020) due to a wide use of the metal has resulted in a significant increase in environmental Al levels (Crisponi et al., 2012). The sources of human Al exposure may include diet (Tietz et al., 2019), being responsible for 95% of total body Al (Goulle and Grangeot-Keros, 2020), drinking water (Krupinska, 2020), air (Exley, 2013), as well as cosmetics (Crisponi et al., 2012, 2013) and medicinal drugs, namely antacids (Klotz et al., 2017). Involvement in Al processing industry may also result in occupational Al exposure (Skalny et al., 2018). Earlier studies demonstrated that vaccination could be considered as a source of Al exposure due to the presence of aluminium adjuvants that are currently not widely used thus reducing the risk of vaccine-associated Al exposure (Goulle and Grangeot-Keros, 2020). Being a non-essential element, Al was shown to be toxic for humans (Exley, 2013), resulting in adverse health effects (Crisponi et al., 2011) including bone pathology (Klein, 2019) and breast cancer (Darbre et al., 2013). Our data also demonstrated the association between obesity (Tinkov et al., 2019), laboratory markers of metabolic syndrome and Al exposure markers (Skalnaya et al., 2018). However, the existing data on adverse effects of Al exposure are limited (Krewski et al., 2007). Recent studies have demonstrated that the brain may be considered as the target for Al toxicity (Exley, 2014), resulting in neurodegenerative (Exley, 2013; Shaw et al., 2014) and neurodevelopmental disorders (Blaylock, 2012). Recent detailed studies by Exley and the coauthors have highlighted the association between brain Al accumulation and neurological disorders including Alzheimer’s disease, multiple sclerosis and autism spectrum disorder (Exley and Clarkson, 2020; Mirza et al., 2017; Mold et al., 2018). Speciation analysis using hyphenated techniques demonstrated that Al exposure induces a specific bioligand response in Al-exposed neuronal cells (Polec-Pawlak et al., 2004). However, the particular mechanisms of Al neurotoxicity and their role in Al-associated neurological disorders are still debatable (Morris et al., 2017). This chapter will provide an update on the particular mechanisms of Al neurotoxicity that may be used as targets for development of therapeutic strategies. Generally, the neurotoxic effect of Al exposure is mediated by its common toxic properties including prooxidant, proinflammatory, proapoptotic activity that are reported for a variety of cell lines and tissues, as well as more specific “neurotropic” effects namely interference with neurotransmitter metabolism and neuronal cytoskeleton.

Polymorphisms of neurotransmitter metabolism genes were studied in patients with prostate cancer (PC) characterized by either reduced or extended serum prostate-specific antigen doubling time (PSADT) corresponding to unfavorable and favorable disease prognosis respectively. The 'unfavorable prognosis' group (40 cases) was defined by PSADT ≤ 2 months, whereas patients in the 'favorable prognosis' group (67 cases) had PSADT ≥ 30 months. The following gene polymorphisms known to be associated with neuropsychiatric disorders were investigated: a) the STin2 VNTR in the serotonin transporter SLC6A4 gene; b) the 30-bp VNTR in the monoamine oxidase A MAOA gene; c) the Val158Met polymorphism in the catechol-ortho-methyltransferase COMT gene; d) the promoter region C-521T polymorphism and the 48 VNTR in the third exon of the dopamine receptor DRD4 gene. The STin2 12R/10R variant of the SLC6A4 gene (OR = 2.278; 95% CI = 0.953-5.444) and the -521T/T homozygosity of the DRD4 gene (OR = 1.579; 95% CI = 0.663-3.761) tended to be overrepresented in PC patients with unfavorable disease prognosis. These gene variants are regarded as protective against schizophrenia, and the observed trend may be directly related to a reduced PC risk described for schizophrenia patients. These results warrant further investigation of the potential role of neurotransmitter metabolism gene polymorphisms in PC pathogenesis.

Caste differentiation in social hymenopterans is an intriguing example of phenotypic plasticity. However, the co-ordination among gene regulatory factors to mediate caste differentiation remains inconclusive. In this study, we determined the role of gene regulation and related epigenetic processes in pre-imaginal caste differentiation in the primitively eusocial bumblebee Bombus terrestris. By combining RNA-Seq data from Illumina and PacBio and accurately quantifying methylation at whole-genomic base pair resolution, we found that queens, workers, and drones mainly differentiate in gene expression but not in alternative splicing and DNA methylation. Gynes are the most distinct with the lowest global level of whole-genomic methylation and with the largest number of caste-specific transcripts and alternative splicing events. By contrast, workers exhibit few uniquely expressed or alternatively spliced genes. Moreover, several genes involved in hormone and neurotransmitter metabolism are related to caste differentiation, whereas several neuropeptides are linked with sex differentiation. Despite little genome-wide association among differential gene expression, splicing, and differential DNA methylation, the overlapped gene ontology (GO) terms point to nutrition-related activity. Therefore, variations in gene regulation correlate with the behavioral differences among castes and highlight the specialization of toolkit genes in bumblebee gynes at the beginning of the adult stage.

Inherited disorders of neurotransmitter metabolism are rare neurodevelopmental diseases presenting with movement disorders and global developmental delay. This study presents the results of the first standardized deep phenotyping approach and describes the clinical and biochemical presentation at disease onset as well as diagnostic approaches of 275 patients from the registry of the International Working Group on Neurotransmitter related Disorders. The results reveal an increased rate of prematurity, a high risk for being small for gestational age and for congenital microcephaly in some disorders. Age at diagnosis and the diagnostic delay are influenced by the diagnostic methods applied and by disease-specific symptoms. The timepoint of investigation was also a significant factor: delay to diagnosis has decreased in recent years, possibly due to novel diagnostic approaches or raised awareness. Although each disorder has a specific biochemical pattern, we observed confounding exceptions to the rule. The data provide comprehensive insights into the phenotypic spectrum of neurotransmitter disorders., We thank all patients and their families for their contributions to this study and for their trust. T.H. and J.K. were supported the grant from the Ministry of Health of the Czech Republic RVO-VFN 64165 GJIH-0599-00-7-846 and ProgresQ26/LF1. A.G.C. and N.J.P. are supported by FIS P118/00111 “Instituto de Salud Carlos III (ISCIII)” and “Fondo Europeo de desarrollo regional (FEDER)”. T.O., K.J., G.F.H. and O.K.H. were supported in parts by the Dietmar Hopp Foundation, St. Leon-Rot, Germany. M.A.K. is funded by an NIHR Professorship, the Sir Jules Thorn Award for Biomedical Research and the Rosetrees trust. M.V. is supported by Stichting Stofwisselkracht Grant. D.H. acknowledges funding by the Molecular Diagnostics Program of the National Center for Tumor Diseases (NCT) Heidelberg.

This study examines the effects of acute pharmacological modulation of the serotonergic system over zebrafish larvae’s cognitive, basic, and defense locomotor behaviors, using a medium to high throughput screening assay. Furthermore, the relationship between behavior, enzyme activity related to neurotransmitter metabolism, neurotransmitter levels, and gene expression was also determined. Modulation of larvae serotonergic system was accomplished by 24 h exposure to single and opposite pharmacodynamics co-exposure to three model psychopharmaceuticals with antagonistic and agonistic serotonin signaling properties: 2.5 mM 4-Chloro-DL-phenylalanine (PCPA) and 5 µM deprenyl and 0.5 µM fluoxetine, respectively. Similar behavioral outcome was observed for deprenyl and fluoxetine, which was reflected as hypolocomotion, decrease in larvae defensive responses, and cognitive impairment. Contrarily, PCPA induced hyperlocomotion and increase in larvae escape response. Deprenyl exposure effects were more pronounced at a lower level of organization than fluoxetine, with complete inhibition of monoamine oxidase (MAO) activity, dramatic increase of 5-HT and dopamine (DA) levels, and downregulation of serotonin synthesis and transporter genes. PCPA showed mainly effects over serotonin and dopamine’s main degradation metabolites. Finally, co-exposure between agonistic and antagonist serotonin signaling drugs reviled full recovery of zebrafish impaired locomotor and defense responses, 5-HT synthesis gene expression, and partial recovery of 5-HT levels. The findings of this study suggest that zebrafish larvae can be highly sensitive and a useful vertebrate model for short-term exposure to serotonin signaling changes., This work was supported by the “Agencia Estatal de Investigación” from the Spanish Ministry of Science and Innovation and the IDAEA-CSIC, a Centre of Excellence Severo Ochoa (CEX2018-000794-S), through the SYNERGY Project “Environmental risk of complex mixtures of emerging persistent and mobile chemicals in aquatic ecosystems (MixPersiRisk)” financed with Severo Ochoa funds. The work was partially supported by the network of recognized research groups by the Catalan Government (2017 SGR_902).