Genetic Advancements in Infantile Epileptic Spasms Syndrome and Opportunities for Precision Medicine

Genes, Journal Year: 2024, Volume and Issue: 15(3), P. 266 - 266

Published: Feb. 21, 2024

Infantile epileptic spasms syndrome (IESS) is a devastating developmental encephalopathy (DEE) consisting of spasms, as well one or both regression stagnation and hypsarrhythmia on EEG. A myriad aetiologies are associated with the development IESS; broadly, 60% cases thought to be structural, metabolic infectious in nature, remainder genetic unknown cause. Epilepsy genetics growing field, over 28 copy number variants 70 single gene pathogenic related IESS have been discovered date. While not exhaustive, some most commonly reported include trisomy 21 genes such

Language: Английский

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Selective inhibition of excitatory synaptic transmission alters the emergent bursting dynamics of in vitro neural networks

Frontiers in Neural Circuits, Journal Year: 2023, Volume and Issue: 17

Published: Feb. 16, 2023

Neurons in vitro connect to each other and form neural networks that display emergent electrophysiological activity. This activity begins as spontaneous uncorrelated firing the early phase of development, functional excitatory inhibitory synapses mature, typically emerges network bursts. Network bursts are events coordinated global activation among many neurons interspersed with periods silencing important for synaptic plasticity, information processing, computation. While bursting is consequence balanced excitatory-inhibitory (E/I) interactions, mechanisms underlying their evolution from physiological potentially pathophysiological states, such decreasing or increasing synchrony, still poorly understood. Synaptic activity, especially related maturity E/I transmission, known strongly influence these processes. In this study, we used selective chemogenetic inhibition target disrupt transmission study response recovery over time. We found time, resulted increases both burstiness synchrony. Our results indicate disruption during development likely affected which an overall decrease at later stages. These findings lend support importance balance maintaining dynamics and, conceivably, processing capacity networks.

Language: Английский

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Milestone review: GABA, from chemistry, conformations, ionotropic receptors, modulators, epilepsy, flavonoids, and stress to neuro‐nutraceuticals

Journal of Neurochemistry, Journal Year: 2024, Volume and Issue: 168(7), P. 1179 - 1192

Published: Feb. 21, 2024

Abstract Arising out of a PhD project more than 50 years ago to synthesise analogues the neurotransmitter GABA, series new chemical entities were found have selective actions on ionotropic GABA receptors. Several these neurochemicals are now commercially available. A subtype receptors was discovered that could be target for treatment myopia, facilitation learning and memory, improvement post‐stroke motor recovery. The development over many demonstrates importance with which investigate aspects illustrates significance collaboration between chemists biologists in neurochemistry. Vital improvements synthetic organic chemistry use functional human expressed oocytes. Current interest includes clinical subtype‐specific agents role gain‐of‐function receptor variants epilepsy. Dietary flavonoids cross blood–brain barrier influence brain function. Natural had range effects receptors, ranging from positive, silent, negative allosteric modulators, even second‐order modulation first‐order modulators. Flavonoids been called “a family benzodiazepines.” Like benzodiazepines, reduce stress. Stress produces changes may because endogenous such as neurosteroids corticosteroids. also occurs naturally diet leading studies oral This finding has resulted related neuro‐nutraceuticals. systems gut microbiome essential studies. GABA‐enriched beverages foodstuffs an area considerable scientific commercial interest. is deceptively simple can take up shapes, underlie its complex functions. need further highlights continuing biologists. image

Language: Английский

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GABA system as the cause and effect in early development

Neuroscience & Biobehavioral Reviews, Journal Year: 2024, Volume and Issue: 161, P. 105651 - 105651

Published: April 4, 2024

Language: Английский

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Oxytocin, GABA, and dopamine interplay in autism

Endocrine Regulations, Journal Year: 2024, Volume and Issue: 58(1), P. 105 - 114

Published: Jan. 1, 2024

Oxytocin plays an important role in brain development and is associated with various neurotransmitter systems the brain. Abnormalities production, secretion, distribution of oxytocin brain, at least during some stages development, are critical for pathogenesis neuropsychiatric diseases, particularly autism spectrum disorder. The etiology includes changes local sensory dopaminergic areas which also supplied by hypothalamic sources oxytocin. It very to understand their mutual relationship. In this review, relationship several components system, gamma-aminobutyric acid (GABA) inhibitory neurotransmission alterations disorder discussed. Special attention has been paid results describing a reduced expression GABAergic markers context models autism. presumed that altered neurotransmission, due absence or dysfunction certain developmental stages, disinhibits signaling contributes symptoms.

Language: Английский

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GABAergic system and chloride cotransporters as potential therapeutic targets to mitigate cell death in ischemia

Journal of Neuroscience Research, Journal Year: 2024, Volume and Issue: 102(5)

Published: May 1, 2024

Gamma aminobutyric acid (GABA) is a critical inhibitory neurotransmitter in the central nervous system that plays vital role modulating neuronal excitability. Dysregulation of GABAergic signaling, particularly involving cotransporters NKCC1 and KCC2, has been implicated various pathologies, including epilepsy, schizophrenia, autism spectrum disorder, Down syndrome, ischemia. facilitates chloride influx, whereas KCC2 mediates efflux via potassium gradient. Altered expression function these have associated with excitotoxicity, inflammation, cellular death ischemic events characterized by reduced cerebral blood flow, leading to compromised tissue metabolism subsequent cell death. inhibition emerged as potential therapeutic approach attenuate intracellular accumulation mitigate damage during events. Similarly, targeting which regulates efflux, holds promise for improving outcomes reducing under conditions. This review emphasizes roles GABA, NKCC1, pathologies their targets. Inhibiting or activity represents promising strategy damage, preventing neurological following Furthermore, exploring interactions between natural compounds NKCC1/KCC2 provides additional avenues interventions injury.

Language: Английский

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The emergence of antidepressant drugs targeting GABAA receptors: A concise review

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 228, P. 116481 - 116481

Published: Aug. 13, 2024

Depression is among the most common psychiatric illnesses, which imposes a major socioeconomic burden on patients, caregivers, and public health system. Treatment with classical antidepressants (e.g. tricyclic selective serotonine reuptake inhibitors), primarily affect monoaminergic systems has several limitations, such as delayed onset of action moderate efficacy in relatively large proportion depressed patients. Furthermore, depression highly heterogeneus, its different subtypes, including post-partum depression, involve distinct neurobiology, warranting differential approach to pharmacotherapy. Given these shortcomings, need for novel that are superior faster fully justified. The development market introduction rapid-acting accelerated recent years. Some new act through GABAergic In this review, we discuss discovery, efficacy, limitations treatment classic antidepressants. We provide detailed discussion neurotransmission, special focus GABA

Language: Английский

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Perinatal exposure to pesticides alters synaptic plasticity signaling and induces behavioral deficits associated with neurodevelopmental disorders

Cell Biology and Toxicology, Journal Year: 2022, Volume and Issue: 39(5), P. 2089 - 2111

Published: Feb. 8, 2022

Increasing evidence from animal and epidemiological studies indicates that perinatal exposure to pesticides cause developmental neurotoxicity may increase the risk for psychiatric disorders such as autism intellectual disability. However, underlying pathogenic mechanisms remain largely elusive. This work was aimed at testing hypothesis different classes of hijacks intracellular neuronal signaling contributing synaptic behavioral alterations associated with neurodevelopmental (NDD). Low concentrations organochlorine (dieldrin, endosulfan, chlordane) organophosphate (chlorpyrifos its oxon metabolite) were chronically dosed ex vivo (organotypic rat hippocampal slices) or in (perinatal rats), then biochemical, electrophysiological, behavioral, proteomic performed. All tested caused prolonged activation MAPK/ERK pathway a concentration-dependent manner. Additionally, some them impaired metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD). In case pesticide chlordane, effect attributed chronic modulation signaling. These reproduced following chlordane chlorpyrifos-oxon, also prototypical phenotypes NDD, including motor development, increased anxiety, social memory deficits. Lastly, analysis revealed these differentially regulate expression proteins hippocampus pivotal roles brain development signaling, which are NDD. Based on results, we propose novel mechanism dysfunction, involving overactivation MAPK mGluR-LTD, shared by have important implications

Language: Английский

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Untargeted Metabolomics reveals Doenjang metabolites affected by manufacturing process and microorganisms

Food Research International, Journal Year: 2022, Volume and Issue: 157, P. 111422 - 111422

Published: May 26, 2022

Doenjang is a traditional Korean fermented soybean-based food that now produced industrially as and modernized Doenjang, depending on the conditions of manufacturing process. In this study, effect production process metabolites was analyzed using untargeted capillary electrophoresis time-of-flight mass spectrometry (CE-TOF/MS). Of 247 detected in 19 three samples, level 55 were significantly different between two groups. The S-plot orthogonal projection to latent structures-discriminant analysis (OPLS-DA) revealed nine compounds (tryptamine, 2-phenylethylamine, citrulline, gamma-aminobutyric acid, putrescine, tyramine, 2-aminoisobutyric stachydrine, N5-ethylglutamine) highly distributed group, six (arginine, citric choline, cytidine, hypoxanthine, glucaric acid) considered distinguishable group. Microbial community indicated levels these altered by presence Bacillus spp., Enterococcus faecium, Tetragenococcus halophilus, Aspergillus oryzae, Penicillium Saccharomyces cerevisiae. These findings will give better understanding influence terms both microbial activity metabolite profiles.

Language: Английский

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Acceleration of GABA-switch after early life stress changes mouse prefrontal glutamatergic transmission

Neuropharmacology, Journal Year: 2023, Volume and Issue: 234, P. 109543 - 109543

Published: April 14, 2023

Early life stress (ELS) alters the excitation-inhibition-balance (EI-balance) in various rodent brain areas and may be responsible for behavioral impairment later life. The EI-balance is (amongst others) influenced by switch of GABAergic transmission from excitatory to inhibitory, so-called "GABA-switch". Here, we investigated how ELS affects GABA-switch mouse infralimbic Prefrontal Cortex layer 2/3 neurons, using limited-nesting-and-bedding model. In mice, occurred already between postnatal day (P) 6 P9, as opposed P15–P21 controls. This was associated with increased expression inward chloride transporter NKCC1, compared outward KCC2, both which are important intracellular concentration and, hence, GABA reversal potential (Erev). Chloride transporters not only regulating postsynaptically, but also presynaptically. Depending on Erev GABA, presynaptic GABAA receptor stimulation causes a depolarization or hyperpolarization, thereby enhanced reduced fusion glutamate vesicles respectively, turn changing frequency miniature postsynaptic currents (mEPSCs). accordance, bumetanide, blocker shifted towards more hyperpolarized levels P9 control mice mEPSC frequency. Other modulators transporters, e.g. VU0463271 (a KCC2 antagonist) aldosterone -which increases NKCC1 expression-did affect did increase We conclude that accelerated after ELS, affecting pre- homeostasis, former altering glutamatergic transmission. considerably development.

Language: Английский

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