New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: I. Role of GABA as a Modulator of Seizure Activity and Recently Approved Medications Acting on the GABA System

CNS Drugs, Journal Year: 2023, Volume and Issue: 37(9), P. 755 - 779

Published: Aug. 21, 2023

γ-Aminobutyric acid (GABA) is the most prevalent inhibitory neurotransmitter in mammalian brain and has been found to play an important role pathogenesis or expression of many neurological diseases, including epilepsy. Although GABA can act on different receptor subtypes, component system that critical modulation seizure activity

Language: Английский

---

Fundamental Neurochemistry Review: GABA_A receptor neurotransmission and epilepsy: Principles, disease mechanisms and pharmacotherapy

Journal of Neurochemistry, Journal Year: 2023, Volume and Issue: 165(1), P. 6 - 28

Published: Jan. 22, 2023

Abstract Epilepsy is a common neurological disorder associated with alterations of excitation‐inhibition balance within brain neuronal networks. GABA A receptor neurotransmission the most prevalent form inhibitory and strongly implicated in both pathophysiology treatment epilepsy, serving as primary target for antiseizure medications over century. It now established that exerts multifaceted influence through an array subtypes extends far beyond simply negating excitatory activity. As role circuits elaborated, this will enable development precision therapies correct network dysfunction underlying epileptic pathology. image

Language: Английский

---

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

Infancy, Journal Year: 2024, Volume and Issue: unknown

Published: March 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.

Language: Английский

---

The NKCC1 inhibitor bumetanide restores cortical feedforward inhibition and lessens sensory hypersensitivity in early postnatal fragile X mice.

Biological Psychiatry, Journal Year: 2024, Volume and Issue: unknown

Published: June 1, 2024

Language: Английский

---

Hsp47 promotes biogenesis of multi-subunit neuroreceptors in the endoplasmic reticulum

eLife, Journal Year: 2024, Volume and Issue: 13

Published: July 4, 2024

Protein homeostasis (proteostasis) deficiency is an important contributing factor to neurological and metabolic diseases. However, how the proteostasis network orchestrates folding assembly of multi-subunit membrane proteins poorly understood. Previous proteomics studies identified Hsp47 (Gene: SERPINH1 ), a heat shock protein in endoplasmic reticulum lumen, as most enriched interacting chaperone for gamma-aminobutyric acid type A (GABA ) receptors. Here, we show that enhances functional surface expression GABA receptors rat neurons human HEK293T cells. Furthermore, molecular mechanism study demonstrates acts after BiP HSPA5 preferentially binds folded conformation without inducing unfolded response Therefore, promotes subunit-subunit interaction, receptor process, anterograde trafficking Overexpressing sufficient correct function epilepsy-associated variants also other Cys-loop receptors, including nicotinic acetylcholine serotonin 3 addition its known collagen chaperone, this work establishes plays critical general role maturation neuroreceptors.

Language: Английский

---

KATP channels are necessary for glucose-dependent increases in amyloid-β and Alzheimer’s disease–related pathology

JCI Insight, Journal Year: 2023, Volume and Issue: 8(10)

Published: May 2, 2023

Elevated blood glucose levels, or hyperglycemia, can increase brain excitability and amyloid-β (Aβ) release, offering a mechanistic link between type 2 diabetes Alzheimer's disease (AD). Since the cellular mechanisms governing this relationship are poorly understood, we explored whether ATP-sensitive potassium (KATP) channels, which couple changes in energy availability with excitability, play role AD pathogenesis. First, demonstrate that KATP channel subunits Kir6.2/KCNJ11 SUR1/ABCC8 were expressed on excitatory inhibitory neurons human brain, cortical expression of KCNJ11 ABCC8 changed pathology humans mice. Next, eliminating neuronal activity uncoupled metabolism, Aβ potentially novel mouse model cerebral amyloidosis ablation (i.e., amyloid precursor protein [APP]/PS1 Kir6.2–/– mouse). Using both acute chronic paradigms, Kir6.2-KATP channels metabolic sensors regulate hyperglycemia-dependent increases interstitial fluid levels Aβ, amyloidogenic processing APP, plaque formation, may be dependent lactate release. These studies identify new for suggest pharmacological manipulation holds therapeutic promise reducing patients prediabetes.

Language: Английский

---

SCN1A channelopathies: Navigating from genotype to neural circuit dysfunction

Frontiers in Neurology, Journal Year: 2023, Volume and Issue: 14

Published: April 17, 2023

The SCN1A gene is strongly associated with epilepsy and plays a central role for supporting cortical excitation-inhibition balance through the expression of Na V 1.1 within inhibitory interneurons. phenotype disorders has been conceptualized as driven primarily by impaired interneuron function that predisposes to disinhibition hyperexcitability. However, recent studies have identified gain-of-function variants epilepsy, presence cellular synaptic changes in mouse models point toward homeostatic adaptations complex network remodeling. These findings highlight need understand microcircuit-scale dysfunction contextualize genetic disease mechanisms. Targeting restoration microcircuit properties may be fruitful strategy development novel therapies.

Language: Английский

---

Variations of Aberrant Volume, Activity, and Network Connectivity of Hippocampus in Adolescent Male Rats Exposed to Juvenile Stress

Brain Sciences, Journal Year: 2025, Volume and Issue: 15(3), P. 284 - 284

Published: March 7, 2025

Background: Childhood is a crucial period for brain development, and short-term juvenile stress has demonstrated long-lasting effects on cognitive cellular functions in the hippocampus. However, influence of such brain’s overall network remains unclear. Methods: In this study, we employed functional magnetic resonance imaging (fMRI) to explore transient wild male rats. Pregnant rats were purchased housed specific pathogen-free (SPF) environment, with pups separated by sex postnatal day 21 (PD21). From PD27 PD29, subjected stress, which included forced swimming, elevated platform exposure, restraint stress. Following all animals carefully maintained scanned at 42 days age (PD42) using fMRI. Structural analysis was performed voxel-based morphometry (VBM) assess changes gray matter volume, while activity evaluated through regional homogeneity (ReHo) voxel-wise connectivity. Results: The results showed significant reductions volume several regions group, including periaqueductal (PAG), entorhinal cortex (Ent), dentate gyrus (DG). terms activity, cortical regions, particularly primary somatosensory areas, exhibited decreased whereas increased observed PAG, DG, medulla. Furthermore, connectivity revealed reduction between DG cortex, DG-PAG significantly enhanced. Conclusions: These findings suggest that leads profound alterations both structure function, potentially disrupting emotional regulation memory processing affecting development key regions.

Language: Английский

---

Glioma‑neuronal interactions in tumor progression: Mechanism, therapeutic strategies and perspectives (Review)

International Journal of Oncology, Journal Year: 2022, Volume and Issue: 61(3)

Published: July 11, 2022

An increasing body of evidence has become available to reveal the synaptic and functional integration glioma into brain network, facilitating tumor progression. The novel discovery glioma‑neuronal interactions fundamentally challenged our understanding this refractory disease. present review aimed provide an overview how neuronal activities function through synapses, neurotransmitters, ion channels, gap junctions, microtubes molecules establish communications with glioma, as well a simplified explanation reciprocal effects crosstalk on pathophysiology. In addition, current state therapeutic avenues targeting critical factors involved in glioma‑euronal is discussed clinical trial data for further investigation provided. Finally, newly emerging technologies, including immunomodulation, neural stem cell‑based delivery system, optogenetics techniques co‑culture neuron organoids are proposed, which may pave way towards gaining deeper insight both mechanisms associated neuron‑ glioma‑communicating networks development strategies target currently lethal tumor.

Language: Английский

---

Excitatory and inhibitory synapses show a tight subcellular correlation that weakens over development

Cell Reports, Journal Year: 2024, Volume and Issue: 43(7), P. 114361 - 114361

Published: June 18, 2024

Neurons receive correlated levels of excitation and inhibition, a feature that is important for proper brain function. However, how this relationship between excitatory inhibitory inputs established during the dynamic period circuit wiring remains unexplored. Using multiple techniques, including in utero electroporation, electron microscopy, electrophysiology, we reveal tight correlation distribution synapses along dendrites developing CA1 hippocampal neurons. This was present within short dendritic stretches (<20 μm) and, surprisingly, most pronounced early development, sharply declining with maturity. The matching inhibition unexpected, as lacked an active zone when formed exhibited compromised evoked release. We propose form stabilizing scaffold to counterbalance growing levels. diminishes over time, suggesting critical role subcellular balance neuronal function formation.

Language: Английский

---