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

Genes, Год журнала: 2024, Номер 15(3), С. 266 - 266

Опубликована: Фев. 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

Язык: Английский

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Prenatal influences on postnatal neuroplasticity: Integrating DOHaD and sensitive/critical period frameworks to understand biological embedding in early development

Infancy, Год журнала: 2024, Номер unknown

Опубликована: Март 6, 2024

Abstract Early environments can have significant and lasting effects on brain, body, behavior across the lifecourse. Here, we address current research efforts to understand how experiences impact neurodevelopment with a new perspective integrating two well‐known conceptual frameworks – Developmental Origins of Health Disease (DOHaD) sensitive/critical period frameworks. Specifically, consider prenatal characterized in DOHaD model key neurobiological mechanisms periods for adapting learning from postnatal environment. We draw both animal human summarize state knowledge particular substance exposures (psychoactive substances heavy metals) nutritional profiles (protein‐energy malnutrition iron deficiency) each differentially brain circuits' excitation/GABAergic inhibition balance myelination. Finally, highlight directions that emerge this integrated framework, including testing alter timing identifying potential promotional/buffering periods. hope integrative framework considering influences neuroplasticity will stimulate early consequences our brains, behavior, health.

Язык: 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, Год журнала: 2023, Номер 17

Опубликована: Фев. 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.

Язык: Английский

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

Journal of Neurochemistry, Год журнала: 2024, Номер 168(7), С. 1179 - 1192

Опубликована: Фев. 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

Язык: Английский

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GABA system as the cause and effect in early development

Neuroscience & Biobehavioral Reviews, Год журнала: 2024, Номер 161, С. 105651 - 105651

Опубликована: Апрель 4, 2024

Язык: Английский

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

Journal of Neuroscience Research, Год журнала: 2024, Номер 102(5)

Опубликована: Май 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.

Язык: Английский

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Oxytocin, GABA, and dopamine interplay in autism

Endocrine Regulations, Год журнала: 2024, Номер 58(1), С. 105 - 114

Опубликована: Янв. 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.

Язык: Английский

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

Biochemical Pharmacology, Год журнала: 2024, Номер 228, С. 116481 - 116481

Опубликована: Авг. 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

Язык: 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, Год журнала: 2022, Номер 39(5), С. 2089 - 2111

Опубликована: Фев. 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

Язык: Английский

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Untargeted Metabolomics reveals Doenjang metabolites affected by manufacturing process and microorganisms

Food Research International, Год журнала: 2022, Номер 157, С. 111422 - 111422

Опубликована: Май 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.

Язык: Английский

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