Rescue of sharp wave-ripples and prevention of network hyperexcitability in the ventral but not the dorsal hippocampus of a rat model of fragile X syndrome DOI Creative Commons

Leonidas J. Leontiadis,

George Trompoukis,

Giota Tsotsokou

et al.

Frontiers in Cellular Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: Dec. 1, 2023

Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder characterized by intellectual disability and related to autism. FXS caused mutations of the fragile messenger ribonucleoprotein 1 gene (Fmr1) associated with alterations in neuronal network excitability several brain areas including hippocampus. The loss protein affects oscillations, however, effects on hippocampal sharp wave-ripples (SWRs), an endogenous pattern contributing memory consolidation have not been sufficiently clarified. In addition, it still known whether dorsal ventral hippocampus are similarly affected FXS. We used Fmr1 knock-out (KO) rat model electrophysiological recordings from CA1 area adult slices assess spontaneous evoked neural activity. find that SWRs multiunit activity but KO hippocampus, while complex spike bursts remain normal both segments Local increases Furthermore, specifically rats we found increased effectiveness inhibition suppressing excitation upregulation α1GABAA receptor subtype. These changes accompanied striking reduction its susceptibility induced epileptiform propose segment reorganized Fmr1-KO means balanced between ensure generation preventing at same time derailment toward hyperexcitability.

Language: Английский

Tangeretin enhances sedative activity of diazepam in Swiss mice through GABAA receptor interaction: In vivo and in silico approaches DOI
Md. Sakib Al Hasan, Md. Shimul Bhuia, Raihan Chowdhury

et al.

Neuroscience, Journal Year: 2025, Volume and Issue: 572, P. 1 - 10

Published: March 5, 2025

Language: Английский

Citations

3
The Yin and Yang of GABAergic and Glutamatergic Synaptic Plasticity: Opposites in Balance by Crosstalking Mechanisms DOI Creative Commons
Caitlyn A. Chapman, Jessica L. Nuwer, Tija C. Jacob

et al.

Frontiers in Synaptic Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: May 19, 2022

Synaptic plasticity is a critical process that regulates neuronal activity by allowing neurons to adjust their synaptic strength in response changes activity. Despite the high proximity of excitatory glutamatergic and inhibitory GABAergic postsynaptic zones functional integration within dendritic regions, concurrent has historically been underassessed. Growing evidence for pathological disruptions excitation inhibition (E/I) balance neurological neurodevelopmental disorders indicates need an improved, more "holistic" understanding interplay. There continues be long-standing focus on persistent strengthening (excitatory long-term potentiation; eLTP) its role learning memory, although importance potentiation (iLTP) depression (iLTD) become increasingly apparent. Emerging further points dynamic dialogue between synapses, but much remains understood regarding mechanisms extent this exchange. In mini-review, we explore calcium signaling crosstalk play regulating excitability. We examine current knowledge synapse responses perturbances activity, with induced short-term pharmacological treatments which act either enhance or reduce excitability via ionotropic receptor regulation culture. To delve deeper into potential crosstalk, discuss influence key regulatory proteins, including kinases, phosphatases, structural/scaffolding proteins. Finally, briefly suggest avenues future research better understand synapses.

Language: Английский

Citations

41
Epileptogenesis in tuberous sclerosis complex-related developmental and epileptic encephalopathy DOI Creative Commons
Eleonora Aronica, Nicola Specchio, Mark J. Luinenburg

et al.

Brain, Journal Year: 2023, Volume and Issue: 146(7), P. 2694 - 2710

Published: Feb. 20, 2023

Abstract Epileptogenesis in infants with tuberous sclerosis complex (TSC) is a gradual and dynamic process, leading to early onset difficult-to-treat seizures. Several cellular, molecular pathophysiologic mechanisms, including mammalian target of rapamycin (mTOR) dysregulation, GABAergic dysfunction abnormal connectivity, may play role this epileptogenic process also contribute the associated developmental encephalopathy. Disease-specific antiseizure medications or drugs targeting mTOR pathway have proved be effective TSC-associated epilepsy. Pre-symptomatic administration vigabatrin, drug, delays seizure reduces risk subsequent epileptic encephalopathy, such as infantile spasms syndrome Lennox–Gastaut syndrome. Everolimus, rapamycin-derived inhibitor, frequency, especially younger patients. This evidence suggests that everolimus should considered course Future trials are needed optimize use determine whether earlier correction dysregulation can prevent progression encephalopathies mitigate their severity TSC. Clinical several other potential (cannabidiol ganaxolone) contributing mechanisms underway. review provides an overview different biological occurring parallel interacting throughout life course, even beyond individuals These complexities highlight challenges faced preventing treating TSC-related

Language: Английский

Citations

40
Parvalbumin Interneuron Dysfunction in Neurological Disorders: Focus on Epilepsy and Alzheimer’s Disease DOI Open Access
Beulah Leitch

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(10), P. 5549 - 5549

Published: May 19, 2024

Parvalbumin expressing (PV+) GABAergic interneurons are fast spiking neurons that provide powerful but relatively short-lived inhibition to principal excitatory cells in the brain. They play a vital role feedforward and feedback synaptic inhibition, preventing run away excitation neural networks. Hence, their dysfunction can lead hyperexcitability increased susceptibility seizures. PV+ also key players generating gamma oscillations, which synchronized oscillations associated with various cognitive functions. interneuron particularly vulnerable aging degeneration has been decline memory impairment dementia Alzheimer’s disease (AD). Overall, of disrupts normal excitatory/inhibitory balance within specific neurocircuits brain thus linked wide range neurodevelopmental neuropsychiatric disorders. This review focuses on dysfunctional inhibitory generation epileptic seizures potential as targets design future therapeutic strategies treat these Recent research using cutting-edge optogenetic chemogenetic technologies demonstrated they be selectively manipulated control restore activity brains animal models. suggests could important developing treatments for patients epilepsy comorbid disorders, such AD, where directly deficits.

Language: Английский

Citations

12
Chloride ions in health and disease DOI Open Access
Satish K. Raut,

K.G Singh,

Shridhar Sanghvi

et al.

Bioscience Reports, Journal Year: 2024, Volume and Issue: 44(5)

Published: April 4, 2024

Chloride is a key anion involved in cellular physiology by regulating its homeostasis and rheostatic processes. Changes Cl- concentration result differential regulation of functions such as transcription translation, post-translation modifications, cell cycle proliferation, volume, pH levels. In intracellular compartments, modulates the function lysosomes, mitochondria, endosomes, phagosomes, nucleus, endoplasmic reticulum. extracellular fluid (ECF), present blood/plasma interstitial compartments. A reduction levels ECF can volume contraction. physiological principal compensatory ion for movement major cations Na+, K+, Ca2+. Over past 25 years, we have increased our understanding signaling mediated Cl-, which has helped molecular metabolic changes observed pathologies with altered Here, review various organs channels responsible transportation, recent information on roles.

Language: Английский

Citations

10
Kynurenine Pathway in Epilepsy: Unraveling Its Role in Glutamate Excitotoxicity, GABAergic Dysregulation, Neuroinflammation, and Mitochondrial Dysfunction DOI
Manpreet Kaur,

Pratyush Porel,

Ronak Y. Patel

et al.

Neurotoxicity Research, Journal Year: 2025, Volume and Issue: 43(2)

Published: March 28, 2025

Language: Английский

Citations

1
Autism spectrum disorder and GABA levels in children with succinic semialdehyde dehydrogenase deficiency DOI
Itay Tokatly Latzer, Ellen Hanson, Mariarita Bertoldi

et al.

Developmental Medicine & Child Neurology, Journal Year: 2023, Volume and Issue: 65(12), P. 1596 - 1606

Published: May 28, 2023

To elucidate the etiological aspects of autism spectrum disorder (ASD) in succinic semialdehyde dehydrogenase deficiency (SSADHD), related to dysregulation γ-aminobutyric acid (GABA) and imbalance excitatory inhibitory neurotransmission.In this prospective, international study, individuals with SSADHD underwent neuropsychological assessments, as well biochemical, neurophysiological, neuroimaging evaluations.Of 29 (17 females) enrolled (median age [IQR] 10 years 5 months [5 11 months-18 1 month]), 16 were diagnosed ASD. ASD severity significantly increased (r = 0.67, p < 0.001) but was inversely correlated plasma GABA -0.67, γ-hydroxybutyrate levels -0.538, 0.004), resting motor threshold measured by transcranial magnetic stimulation -0.44, 0.03). A discriminative analysis indicated that an older than 7 2 (p 0.004) less 2.47 μM 0.01) are values beyond which likelihood presenting is increased.ASD prevalent not universal SSADHD, it can be predicted lower GABA-related metabolites. increases loss cortical inhibition. These findings add insight into pathophysiology may facilitate its early diagnosis intervention SSADHD.

Language: Английский

Citations

16
Is tuberous sclerosis complex-associated autism a preventable and treatable disorder? DOI

Paolo Curatolo,

Mirte Scheper,

Leonardo Emberti Gialloreti

et al.

World Journal of Pediatrics, Journal Year: 2023, Volume and Issue: 20(1), P. 40 - 53

Published: Oct. 25, 2023

Language: Английский

Citations

14
GABAergic system and chloride cotransporters as potential therapeutic targets to mitigate cell death in ischemia DOI
Amary Nascimento,

Danniel Pereira‐Figueiredo,

Vladimir Pedro Peralva Borges-Martins

et al.

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

Citations

6
GABAA and GABAB Receptors Mediate GABA-Induced Intracellular Ca2+ Signals in Human Brain Microvascular Endothelial Cells DOI Creative Commons
Sharon Negri, Francesca Scolari, Mauro Vismara

et al.

Cells, Journal Year: 2022, Volume and Issue: 11(23), P. 3860 - 3860

Published: Nov. 30, 2022

Numerous studies recently showed that the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), can stimulate cerebral angiogenesis and promote neurovascular coupling by activating ionotropic GABAA receptors on cerebrovascular endothelial cells, whereas role of metabotropic GABAB is still unknown. Preliminary evidence receptor stimulation induce an increase in Ca2+ levels, but underlying signaling pathway remains to be fully unraveled. In present investigation, we found GABA evoked a biphasic elevation [Ca2+]i was initiated inositol-1,4,5-trisphosphate- nicotinic adenine dinucleotide phosphate-dependent release from neutral acidic stores, respectively, sustained store-operated entry. were both required trigger response. Unexpectedly, signal flux-independent manner via receptors. Likewise, full response requires functional This study, therefore, sheds novel light molecular mechanisms which controls at unit.

Language: Английский

Citations

20