Objective: Glutamic acid decarboxylase, an enzyme in GABA biosynthesis, is encoded by the GAD1 gene, the transcriptional activity of which is affected by the rs3749034 polymorphism. The aim was to investigate the effects of rs3749034 on cognitive event-related potentials (P300) in healthy subjects and schizophrenic patients. Methods: Determination of rs3749034 polymorphism was performed in 89 healthy volunteers and 109 schizophrenic patients (males). Two-stimulus oddball task performance and P300 auditory evoked potentials were analyzed and patient symptomatology was assessed using the Positive and Negative Syndrome Scale (PANSS). Results: An increased frequency of C allele carriers was disclosed in patients. In controls, superior task performance was observed in cytosine thymine carriers, while a greater P300 amplitude and shorter latency were found in C/C carriers. Analogous effects were found in patients with a disease onset before 25 years of age. Higher N5 and lower P3 and G5 PANSS scales were revealed in C/C homozygotes. Conclusions: The findings substantiate an involvement of GABA-ergic mechanisms in maintaining an optimal excitatory-inhibitory balance and an association of rs3749034 with early-onset disorder and negative symptoms of schizophrenia. Significance: These results are important for understanding underlying mechanisms and the development of evidence-based methods for assessing the risk of schizophrenia. (c) 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

The behavioral effects of α-synuclein oligomers were studied at various times after its chronic intranasal administration to 75-day-old C57BL/6J mice in comparison with the dynamics of changes in the transcriptional activity of caspases genes (Casp9, Casp8, and Casp3) in the hippocampus, frontal cortex, and cerebellum. The negative effects of α-synuclein oligomers on exploratory activity and short-term memory in the novel object recognition test were most pronounced after 90 days from the end of administration, while after 1 and 270 days, partial compensation of the studied cognitive functions was observed. Analysis of the expression of caspase genes suggests that early compensatory mechanisms are associated with suppression of the effector caspase-3 gene expression along with increased activity of the genes encoding initiator caspases-9 and -8. Late compensation processes are associated with a decrease in the activity of initiator caspases in the frontal cortex and cerebellum.

Образование нейротоксических амилоидогенных форм белка альфа-синуклеина (α-син) является ключевым молекулярным звеном патогенеза ряда нейродегенеративных заболеваний, включая болезнь Паркинсона (БП). Есть основания полагать, что развитие когнитивных нарушений на субклиническом уровне предшествует манифестации моторных симптомов БП, причем имеются весомые свидетельства сопряженности этих нарушений с дезорганизацией механизмов регуляции нейрогенеза в зрелом мозге. Однако сведения о долгосрочном влиянии амилоидогенных форм α-син на динамику когнитивной активности и молекулярные процессы в трансляционных моделях синуклеинопатий практически отсутствуют. Цель работы – изучение динамики эффектов интраназального введения олигомеров α-син молодым половозрелым животным в отношении исследовательской активности и эпизодической памяти, а также экспрессии генов S100A6 и ASCL1, регулирующих различные стадии нейрогенеза, в гиппокампе, фронтальной коре и мозжечке с одновременной оценкой структурно-функциональных связей между поведенческими и молекулярными показателями. Материалы и методы. Самцам мышей С57BL/6J 2,5-месячного возраста в течение 14 дней интраназально вводили раствор полученных in vitro олигомеров рекомбинантного α-син либо физиологический раствор с последующим тестированием поведения в модели «Распознавание нового объекта» в возрасте 3, 6 и 12 месяцев. В каждой из возрастных точек определяли экспрессию генов S100A6 и ASCL1 в гиппокампе, фронтальной коре и мозжечке методом полимеразной цепной реакции. Результаты исследования. В возрасте 3 месяцев у мышей, получавших олигомеры α-син, обнаружено снижение относительно контроля скорости передвижения в условиях повышения новизны контекста при сохранности других показателей поведения, а также возрастание экспрессии генов S100A6 и ASCL1 во фронтальной коре и снижение активности гена ASCL1 в мозжечке. В возрасте 6 месяцев у животных экспериментальной группы наблюдалось снижение исследовательской активности и эпизодической памяти при отсутствии отличий от контроля по показателям транскрипционной активности исследованных генов. В 12 месяцев в опытной группе выявлены нарушения инициации исследовательского поведения и эпизодической памяти; наблюдалось также снижение экспрессии гена ASCL1 во фронтальной коре и мозжечке. Выявленные в различных временных точках корреляционные связи молекулярных и поведенческих показателей свидетельствуют о возможной компенсаторной/протекторной роли изменений экспрессии гена ASCL1 после введения олигомеров α-син у 3-месячных животных. Заключение. Результаты проведенных исследований показывают, что динамика развития когнитивного дефицита после введения амилоидогенных форм α-син определяется не только их токсическим воздействием, но также компенсаторными процессами, включающими изменения транскрипционной активности генов, регулирующих процессы нейрогенеза в зрелом мозге. Полученные данные позволяют предположить существование специфичных для определенных возрастных периодов компенсаторных механизмов, связанных с регуляцией стадий пролиферации и дифференцировки нейрогенеза у взрослых животных. Дальнейшие исследования, направленные на выявление таких механизмов, представляются необходимыми для развития персонализированных стратегий профилактики и терапии нейродегенеративных нарушений. The formation of neurotoxic amyloidogenic forms of the protein alpha-synuclein (α-syn) is a key molecular link in the pathogenesis of a number of neurodegenerative diseases, including Parkinson’s disease (PD). There is reason to believe that the development of cognitive impairment at a subclinical level precedes the manifestation of motor symptoms of PD, and there is significant evidence that these disorders are associated with disorganization of the mechanisms regulating neurogenesis in the mature brain. However, information about the long-term influence of amyloidogenic forms of α-syn on the dynamics of cognitive activity and molecular processes in translational models of synucleinopathies are practically absent. The aim of the work is to study the dynamics of the effects of intranasal administration of α-syn oligomers to young sexually mature animals in relation to exploratory activity and episodic memory, as well as the expression of the S100A6 and ASCL1 genes, which regulate various stages of neurogenesis, in the hippocampus, prefrontal cortex and cerebellum with simultaneous assessment of the structural functional connections between behavioral and molecular indicators. Materials and methods. Male C57BL/6J mice, 2.5 months old, were intranasally injected with a solution of recombinant α-syn oligomers or saline for 14 days, followed by behavioral testing in a novel object recognition model at the ages of 3, 6, and 12 months. At each age point, the expression of the S100A6 and ASCL1 genes in the hippocampus, frontal cortex and cerebellum was determined using the polymerase chain reaction method. Results. At the age of 3 months, mice treated with α-syn oligomers showed a decrease in movement speed relative to control under conditions of increasing context novelty while maintaining other behavioral indicators, as well as an increase in the expression of S100A6 and ASCL1 genes in the cortex and a decrease in ASCL1 activity in the cerebellum. At the age of 6 months, animals in the experimental group showed a decrease in exploratory activity and episodic memory, with no differences from the control in terms of transcriptional activity of the studied genes. At 12th months in the experimental group, disturbances in the initiation of exploratory behavior were revealed while maintaining its total duration and episodic memory; there was also a decrease in gene ASCL1 expression in the prefrontal cortex and cerebellum. Correlations of molecular and behavioral parameters identified at different time points indicate a possible compensatory/protective role of changes in gene ASCL1 expression after administration of α-syn in 3-month-old animals. Conclusion. The results of the studies show that the dynamics of the development of cognitive deficit after administration of α-syn is determined not only by the toxic effects of amyloidogenic forms of the protein, but also by compensatory processes, including changes in the transcriptional activity of genes that regulate the processes of neurogenesis in the mature brain. The data obtained also suggest the existence of age-specific compensatory mechanisms associated with the regulation of the cellular proliferation/differentiation stages of neurogenesis. Further research aimed at identifying such mechanisms seems necessary for the development of personalized strategies for the prevention and treatment of neurodegenerative disorders.

In the cerebellum, hippocampus, and prefrontal cortex of mature male Wistar rats with trained spatial navigational skill in the Morris water maze, the transcriptional activity the NAPA gene that regulates the transport and secretion of synaptic vesicles, release of neurotransmitters, and protein degradation was determined by real-time PCR. Animals subjected to forced swimming in a time-matched regime (active control) and naïve rats were used as the comparison groups. Suppression of NAPA gene activity was found in the hippocampus and cerebellum of the active control group, while navigation skill training led to a significant increase in gene expression in all brain structures under study. The findings suggest the existence of specific mechanisms regulating NAPA gene activity during the formation of spatial memory and adaptive behavior under stress conditions.

The activity in the open field, short- and long-term memory in the novel object recognition test, and gait features were evaluated in 6- and 12-month-old male C57BL/6 mice. The levels of norepinephrine, dopamine, serotonin, and their metabolites were determined in the cerebellum and frontal cortex. In the observed age range, a decrease in locomotion speed, impairment of gait initiation and stability, and long-term memory deficit were revealed. In the cerebral cortex, reduced levels of dopamine and its metabolites and accelerated metabolism of all neurotransmitters under study were found. In the cerebellum, the content of all studied monoamines was elevated, while dopamine metabolism was decelerated. Analysis of correlations between the neurochemical and behavioral parameters showed that the mechanisms of compensation of brain functions during the early aging may be associated with an increase in activity of the monoaminergic systems in the cerebellum.

We studied the effects of chronic intranasal administration of amyloidogenic fibrils of the proinflammatory protein S100A9 alone or in combination with glutamate antibodies on the expression of the neuregulin-1 gene (NRG1), a regulator of various physiological processes, in particular, regulation of neurogenesis and apoptosis, in the hippocampus, prefrontal cortex, and cerebellum of aging C57BL/6 mice under conditions of long-term memory disturbances. Under conditions of amnesia induced by S100A9 fibrils, pronounced (>90%) blockade of the expression of the NRG1 gene was found in all cerebral structures. Glutamate antibodies prevented/corrected disturbances in the cerebral expression of the NRG1 gene, thereby maintaining the activity of the NRG1/ErbB molecular signaling system, probably associated with the formation of spatial memory.

Abstract —Parkinson’s disease is a widespread, progressive, age-related neurodegenerative disease. The neurochemical basis of motor and non-motor disorder in Parkinson’s disease is the dysfunction of many neurotransmitter systems of the brain and, first of all, the functional deficit and imbalance of monoaminergic systems, which result from the degradation and death of certain populations of nerve cells caused by misfolding of the α-synuclein protein and the action of its amyloidogenic neurotoxic conformations. Analysis of age-related changes in monoaminergic systems and the development of motor and non-motor disorders at the preclinical and clinical stages of the disease are of particular interest. We studied the effect of α-synuclein oligomers administered intranasally for 14 days on locomotor activity, emotional state, short- and long-term memory, and the content and metabolism of dopamine, serotonin, and norepinephrine in the hippocampus, frontal cortex, and cerebellum of male C57Bl/6 mice at the age of 3 months. In behavioral experiments, the following tests were used: “open field,” “novel object recognition,” “passive avoidance,” and “elevated plus maze.” The content of monoamines and their metabolites in the brain tissue of animals was determined by high performance liquid chromatography with electromagnetic detection. It was found that mice treated with α-synuclein oligomers showed manifestations of affective-like behavior with signs of apathy. The animals showed no disorders in motor activity, short-term and long-term memory, and no changes in anxiety level. Oligomers of α-synuclein caused a significant decrease in the content of dopamine and its metabolites DOPAC and HVA in the frontal cortex, as well as a decrease in the concentration of the dopamine metabolite, 3-MT, and opposite directed changes in serotonin and dopamine metabolism in the hippocampus. However, a significant increase in the content of 3-MT in the cerebellum was recorded. We performed comparative analysis of the data obtained in this work and the results of our previous study of the neurochemical and behavioral effects of α-synuclein oligomers in 6-month-old mice. The results indicate that oligomers of α‑synuclein, when administered chronically intranasally, induce non-motor disorders and neurochemical changes in mice of 3 months of age, which are also observed at the preclinical stage of PD.

We analyzed delayed effect of intranasal administration of anti-glutamate antibodies on mnestic function and tissue concentrations of neurotransmitters in the hippocampus and prefrontal cortex in aging C57BL/6 mice. It was found that after 14-day administration of anti-glutamate antibodies, improvement of the passive avoidance conditioning persisted for 7 days after the treatment was discontinued. In 7 days after discontinuation of treatment, increased content of dopamine and its metabolites as well as aspartic acid and taurine was observed in the hippocampus of mice treated with anti-glutamate antibodies. In the prefrontal cortex, administration of anti-glutamate antibodies had no effect on the levels of neurotransmitters, but increased the concentration of glutamate.

The comprehensive assessment of the effect of the catecholamine-O-methyltransferase (COMT) gene Val 158 Met polymorphism on the antisaccade (AS) performance and the characteristics of slow potentials was carried out in the work. The analysis of saccade characteristics included the side of the stimulus presentation and the saccade direction. The study involved 43 male volunteers. In carriers of val allele, the latency variability (coefficient of variation, K var ) was higher than in carriers of met / met genotype with significant differences for right-side saccades (performed in response to the left stimuli). Along with this, in carriers of val / val genotype, the amplitude of the negative shift associated with cortical activation was increased in the frontal regions of the cortex relative to carriers of the met / met genotype. These results indicate a definite advantage of met / met genotype carriers in AS performance. Specific asymmetries were found for different genotypes: in carriers of met / met homozygote, the errors’ percent was almost twice higher in response to the stimulus at the left than to the stimulus at the right; in carriers of val allele, the latency of saccades and K var for the left stimulus were significantly higher than that for the right one. The analysis showed a relative decrease in the efficiency of the right hemisphere in carriers of met / met genotype, and the left hemisphere in val / val genotype carriers.

The prognostic models assessing the risk of prehypertension in coming 1-2-year period for 30-60-year-old subjects were developed with the help of computer recognition technology using 6 recognition methods. These models are based on the content of molecular markers in blood serum and the risk factors for the development of prehypertension in men and women who had "optimal" BP for last 3 years and in patients with newly diagnosed prehypertension. The models were compared for their prediction power. The most effective model was obtained with gradient boosting method based on the content of molecular markers. It is characterized with a high predictive power (ROC AUC=0.76), specificity (96.4%), and overall accuracy (86.6%) accompanied with close relationship between prognosis and actual symptoms of prehypertension (p=0.001).

The comprehensive assessment of the effect of the catecholamine-O-methyltransferase (COMT) gene Val158Met polymorphism on the antisaccade (AS) performance and the characteristics of slow potentials was carried out in the work. The analysis of saccade characteristics included the side of the stimulus presentation and the saccade direction. The study involved 43 male volunteers. In carriers of val allele, the latency variability (coefficient of variation, Kvar) was higher than in carriers of met/met genotype with significant differences for right-side saccades (performed in response to the left stimuli). Along with this, in carriers of val/val genotype, the amplitude of the negative shift associated with cortical activation was increased in the frontal regions of the cortex relative to carriers of the met/met genotype. These results indicate a definite advantage of met/met genotype carriers in AS performance. Specific asymmetries were found for different genotypes: in carriers of met/met homozygote, the errors’ percent was almost twice higher in response to the stimulus at the left than to the stimulus at the right; in carriers of val allele, the latency of saccades and Kvar for the left stimulus were significantly higher than that for the right one. The analysis showed a relative decrease in the efficiency of the right hemisphere in carriers of met/met genotype, and the left hemisphere in val/val genotype carriers.

Abstract—We studied the effects of intranasal administration of native α-synuclein, whose hyperproduction and misfolding are the key link in the pathogenesis of Parkinson’s disease and other age-related neurodegenerative diseases, on hippocampal neurogenesis, the number of dopaminergic neurons in the substantia nigra, locomotor activity, learning, memory, and anxiety level in ageing animals. The experiments were performed with 12-month-old C57BL/6 male mice which were treated for 14 days with a solution of recombinant native α-synuclein or physiological saline once every 24 hours. To evaluate behavioral indices, the following tests were used: open field, novel object recognition, conditioned passive avoidance response, and elevated plus maze. Proliferating cells, immature neurons, and dopaminergic nerve cells were immunohistochemically detected using antibodies against bromodeoxyuridine, doublecortin, and tyrosine hydroxylase. It was demonstrated that α-synuclein causes a considerable increase in the number of proliferating cells and a decrease in the number of immature neurons in the dentate gyrus the hippocampus, as well as a decrease in the density of dopaminergic neurons in the substantia nigra pars compacta. Mice that received native α-synuclein demonstrated lower locomotion speed, impairments in long-term associative memory, and changes in anxiety-like behavior. We compared the obtained data with the previous results on the effects of α-synuclein oligomers and fibrils under similar experimental protocols. The data are viewed as experimental evidence of the impairment of postnatal neurogenesis during the development of synucleinopathies and support the notion that different α-synuclein conformations cause the development of different neurodegenerative diseases.

Proinflammatory S100A9 protein is a promoter of inflammation-linked neurodegeneration and the Tnfrsf1A gene encodes the TNF receptor 1A that binds TNFα to function as a regulator of inflammation. We studied the effects of chronic intranasal administration of in vitro prepared S100A9 fibrils alone or in combination with anti-glutamate antibodies on the expression of the Tnfrsf1A gene in the hippocampus, prefrontal cortex, and cerebellum of aging C57BL/6 mice under conditions of impaired spatial memory. A differential cerebral pattern of Tnfrsf1A gene activity and its modification by S100A9 fibrillar structures were observed: inhibition of Tnfrsf1A gene expression in the hippocampus and cerebellum and its activation in the prefrontal cortex. Anti-glutamate antibodies normalized the expression of the Tnfrsf1A gene in the prefrontal cortex by affecting the TNF signaling pathway and preventing the development of inflammation.

Intranasal administration of antibodies to glutamate in a dose of 250 μg/kg for two weeks facilitated spatial learning and memory formation in the Morris water maze in aging C57BL/6 mice. In animals treated with glutamate antibodies, the content of serotonin and dopamine metabolites 3-MT and HVA in the hippocampus decreased, but no changes in the metabolism of neurotransmitter acids were revealed. In the prefrontal cortex, dopamine level decreased and the content of its metabolite DOPAC increased; in parallel, an increase in excitatory and inhibitory amino acids (aspartic acid, glutamate, glycine, taurine, and GABA) was observed.

The concentrations of the key factors of molecular pathogenesis of prehypertension (angiotensin II, HLDF24, S100b, endothelin, autoantibodies to these molecules, and VEGF) were analyzed in subjects with optimal BP (<120/80 mm Hg) and prehypertension (120-139/80-89 mm Hg). Comparative and correlation analysis of the levels of these molecules was performed. A statistically significant decrease in HLDF24 level in prehypertension in comparison optimal BP was observed. Specific features and interactions between the studied factors in optimal BP and in prehypertension were studied. The mechanisms underlying the observed associations between serum concentration of HLFF24 and the development of prehypertension were discussed.

Abstract—The pre-fibrillar oligomeric structures of the α-synuclein protein formed during misfolding play an important role in the molecular pathogenesis of Parkinson’s disease and other age-dependent neurodegenerative diseases. We studied the effect of toxic α-synuclein oligomers administered intranasally for 14 days on the motor activity, learning, memory, and anxiety of adult (6-month-old) male C57Bl/6 mice, and on the levels and metabolism of monoamines and neurotransmitter amino acids in the hippocampus and the frontal cortex. We used the open field, passive avoidance, and elevated plus maze tests. The levels of monoamines and their metabolites, and neurotransmitter amino acids in the brain tissue of animals were determined by high performance liquid chromatography with electrochemical detection. It was found that oligomers of α‑synuclein cause an increase in anxiety in adult mice, a pronounced decrease in dopamine levels and oppositely directed changes in dopamine metabolite levels in the hippocampus and frontal cortex. No significant changes were found in learning indices and long-term memory, motor activity of animals, levels of noradrenaline, serotonin, or neurotransmitter amino acids in the studied brain structures after treatment with α-synuclein oligomers. We compared the experimental data and the results of our previous studies on the behavioral and neurochemical effects of oligomeric protein structures in aging 12-month-old mice. The possible mechanisms of the age-dependent effects of the α-synuclein oligomers are discussed.