Development of KCC2 therapeutics to treat neurological disorders DOI Creative Commons
Shilpa D. Kadam, Shane V. Hegarty

Frontiers in Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: Dec. 10, 2024

KCC2 is CNS neuron-specific chloride extruder, essential for the establishment and maintenance of transmembrane gradient, thereby enabling synaptic inhibition within CNS. Herein, we highlight hypofunction as a fundamental conserved pathology contributing to neuronal circuit excitation/inhibition (E/I) imbalances that underly epilepsies, chronic pain, neuro-developmental/-traumatic/-degenerative/-psychiatric disorders. Indeed, downstream both acquired genetic factors, multiple pathologies (e.g., hyperexcitability inflammation) converge impair KCC2-dependent in When occurs, affected neurons are disinhibited due impaired inhibitory responses GABA/glycine. This causes hyperexcitability, disinhibition neuron circuits, disrupted neurological functions. More recently, was identified genetically-validated target epilepsy, intellectual disability, autism spectrum disorder, pathogenic mutations human SLC12A5 gene were linked psychiatric/mood The broad therapeutic utility KCC2-upmodulating drugs relates its critical role determining activity GABAergic neurotransmission, mechanism widely targeted by several drugs. However, cases neurotransmission can be depolarizing/excitatory, impairing endogenous while also limiting effectiveness existing therapeutics targeting/requiring pathway inhibition. Several preclinical reports have shown upmodulating treatments rescue increase efficacy anti-seizure analgesic medications. Thus, first-in-class KCC2-potentiating therapy would provide novel restoring physiological addressing drug resistance patients with E/I imbalance pathologies. discuss progress toward further work needed develop treat disorder patients.

Language: Английский

Antisocial personality disorder:Failure to balance excitation/inhibition? DOI Creative Commons
Klaus‐Peter Lesch, Nikita Gorbunov

Neuropharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 110321 - 110321

Published: Jan. 1, 2025

Language: Английский

Citations

1
Gestational Duration and Postnatal Age‐Related Changes in Aperiodic and Periodic Parameters in Neonatal and Toddler Electroencephalogram (EEG) DOI Creative Commons
Silja Luotonen, Henry Railo, Henriette Acosta

et al.

Human Brain Mapping, Journal Year: 2025, Volume and Issue: 46(1)

Published: Jan. 1, 2025

ABSTRACT The brain develops most rapidly during pregnancy and early neonatal months. While prior electrophysiological studies have shown that aperiodic activity undergoes changes across infancy to adulthood, the role of gestational duration in periodic remains unknown. In this study, we aimed bridge gap by examining associations between EEG power spectrum both neonates toddlers. This cross‐sectional study involved data from 73 (postnatal age 1–5 days, 40 females) 56 toddlers 2.9–3.2 years, 28 FinnBrain Birth Cohort Study. spectra were parameterized components using SpecParam tool. We tested as well postnatal parameters while including birth weight child sex covariates. For neonates, multilevel models employed, considering different acquisitions (sleep auditory paradigm + sleep), toddlers, regression used only was available. found longer associated with a steeper frequencies Effect especially strong ( β = 0.45, p 0.004), it remained nearly statistically significant 0.061). quadratic association beta center frequency (12.5–30 Hz) found. overall higher females compared males. Offset (calculated curve at 2.5 theta had negative but not Our results suggest may relatively long‐lasting effects on physiology. possible behavioral cognitive consequences these are enticing topics for future research.

Language: Английский

Citations

0
Adjusting the composition of gut microbiota prevents the development of post-stroke depression by regulating the gut-brain axis in mice DOI

Su-ting Jiang,

Mengqing Wang, Li Gao

et al.

Journal of Affective Disorders, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

0
Autism spectrum disorder and various mechanisms behind it DOI

Parisa Rajabi,

Ali Sabbah Noori,

Javad Sargolzaei

et al.

Pharmacology Biochemistry and Behavior, Journal Year: 2024, Volume and Issue: 245, P. 173887 - 173887

Published: Oct. 6, 2024

Language: Английский

Citations

2
A study on the correlation between physical fitness index and executive function in Chinese adolescents DOI
Jinxian Wang, Jian Wu,

Yuanyuan Ma

et al.

Applied Neuropsychology Child, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 10

Published: July 29, 2024

Objective To explore the relationship between physical fitness index and executive function in Chinese adolescents, to provide a reference for improving development of adolescents.

Language: Английский

Citations

1
The effects and mechanisms of Chai Shao Jie Yu Granules on chronic unpredictable mild stress (CUMS)-induced depressive rats based on network pharmacology DOI Creative Commons
Qin Tang,

Haolin Chu,

Nan Sun

et al.

Journal of Ethnopharmacology, Journal Year: 2024, Volume and Issue: 340, P. 119268 - 119268

Published: Dec. 19, 2024

Language: Английский

Citations

1
A novel de novo GABRA2 gene missense variant causing developmental epileptic encephalopathy in a Chinese patient DOI Creative Commons
Li Yang,

Xingyu Wan,

Ran Hua

et al.

Annals of Clinical and Translational Neurology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 31, 2024

Abstract Background Variants in the GABRA2 gene, which encodes α2 subunit of γ‐aminobutyric acid A receptor, have been linked to a rare form developmental and epileptic encephalopathy (DEE) referred as DEE78. Only eight patients reported globally. This study presents clinical presentation genetic analysis Chinese family with child diagnosed DEE78, due novel variant. Methods Genetic diagnosis was performed using trio‐whole exome sequencing, followed by bioinformatics predictions pathogenicity. Structural modeling assessed potential impact mutant plasmid constructed transfected into 293 T cells. Western blotting (WB) used evaluate protein expression, while co‐immunoprecipitation (Co‐IP) analyzed interactions GABRB3 GABRG2 proteins. Immunofluorescence (IF) subcellular localization protein. Results The 6‐year‐old male proband presented seizures starting at age two, along global delay hypotonia. testing revealed heterozygous de novo variant gene (NM_000807: c.923C>T, p.Ala308Val). suggested that this is located within extracellular domain, may disrupt hydrogen bonding GABRG2. WB Co‐IP showed reduced expression impaired interactions, potentially destabilizing pentamer receptor complex. If did not affect localization. Conclusion identified likely pathogenic domain causing DEE phenotype. results expand genotypic phenotypic spectrum ‐related DEE.

Language: Английский

Citations

1
Self-reported cancer-related cognitive impairment is associated with perturbed neurotransmission pathways DOI Creative Commons
Kate Oppegaard, Yvette P. Conley, Steven M. Paul

et al.

Journal of Neural Transmission, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 26, 2024

Language: Английский

Citations

0
High gamma-aminobutyric acid (GABA) producing Enterococcus malodoratus isolated from Protected Denomination of Origin (PDO) cheese DOI Creative Commons
Márcia C. Coelho, Susana C. Ribeiro, F. Xavier Malcata

et al.

International Dairy Journal, Journal Year: 2024, Volume and Issue: unknown, P. 106112 - 106112

Published: Oct. 1, 2024

Language: Английский

Citations

0
Development of KCC2 therapeutics to treat neurological disorders DOI Creative Commons
Shilpa D. Kadam, Shane V. Hegarty

Frontiers in Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: Dec. 10, 2024

KCC2 is CNS neuron-specific chloride extruder, essential for the establishment and maintenance of transmembrane gradient, thereby enabling synaptic inhibition within CNS. Herein, we highlight hypofunction as a fundamental conserved pathology contributing to neuronal circuit excitation/inhibition (E/I) imbalances that underly epilepsies, chronic pain, neuro-developmental/-traumatic/-degenerative/-psychiatric disorders. Indeed, downstream both acquired genetic factors, multiple pathologies (e.g., hyperexcitability inflammation) converge impair KCC2-dependent in When occurs, affected neurons are disinhibited due impaired inhibitory responses GABA/glycine. This causes hyperexcitability, disinhibition neuron circuits, disrupted neurological functions. More recently, was identified genetically-validated target epilepsy, intellectual disability, autism spectrum disorder, pathogenic mutations human SLC12A5 gene were linked psychiatric/mood The broad therapeutic utility KCC2-upmodulating drugs relates its critical role determining activity GABAergic neurotransmission, mechanism widely targeted by several drugs. However, cases neurotransmission can be depolarizing/excitatory, impairing endogenous while also limiting effectiveness existing therapeutics targeting/requiring pathway inhibition. Several preclinical reports have shown upmodulating treatments rescue increase efficacy anti-seizure analgesic medications. Thus, first-in-class KCC2-potentiating therapy would provide novel restoring physiological addressing drug resistance patients with E/I imbalance pathologies. discuss progress toward further work needed develop treat disorder patients.

Language: Английский

Citations

0