Seizures regulate the cation-Cl− cotransporter NKCC1 in a hamster model of epilepsy: implications for GABA neurotransmission DOI Creative Commons
Juan‐Manuel Bonet‐Fernández, Pedro Tranque, José‐Daniel Aroca‐Aguilar

et al.

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

Published: June 22, 2023

The balance between the activity of Na+/K+/Cl- cotransporter (NKCC1) that introduces Cl- into cell and K+/Cl- (KCC2) transports outside is critical in determining inhibitory or excitatory outcome GABA release. Mounting evidence suggests impairment GABAergic neurotransmission plays a crucial role pathophysiology epilepsy, both patients animal models. Previous studies indicate decreased KCC2 expression linked to audiogenic seizures GASH/Sal hamsters, highlighting imbalance can cause neuronal hyperexcitability. In this study, we aimed investigate whether NKCC1 also affected by could, therefore, play hyperexcitability within epilepsy model. protein strain wild type hamsters was analyzed immunohistochemistry Western blotting techniques. Brain regions examined included cortex, hippocampus, hypothalamus, inferior colliculus pons-medulla oblongata, which were evaluated at rest after sound-inducing hamsters. A complementary analysis gene slc12a2 conducted real-time PCR. Finally, mRNA levels glutamate decarboxylase GAD67 measured as an indicator induction caused significant changes epileptic despite similar brain pattern absence seizures. Interestingly, regulation demonstrated regional specificity, exclusively increased hippocampus hypothalamus. Complementary PCR revealed post-transcriptional only addition, modulated region-specific manner. hypothalamus hamster upregulation overlaps with release these during Our results seizure causes dysregulation animals, These observations provide for how affect excitability, support contribution development secondary foci epileptogenic activity.

Language: Английский

New epilepsy therapies in development DOI
Pavel Klein, Rafal M. Kaminski, Matthias J. Koepp

et al.

Nature Reviews Drug Discovery, Journal Year: 2024, Volume and Issue: 23(9), P. 682 - 708

Published: July 22, 2024

Language: Английский

Citations

34
GABAergic neuron-to-glioma synapses in diffuse midline gliomas DOI Creative Commons
Tara Barron, Belgin Yalçın, Minhui Su

et al.

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Language: Английский

Citations

5
Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus DOI Creative Commons
Cameron Sadegh, Huixin Xu, Jason Sutin

et al.

Neuron, Journal Year: 2023, Volume and Issue: 111(10), P. 1591 - 1608.e4

Published: March 8, 2023

Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding this variably progressive condition has hampered the development new therapies beyond serial neurosurgical interventions. Here, we show key role for bidirectional Na-K-Cl cotransporter, NKCC1, in choroid plexus (ChP) mitigate PHH. Mimicking IVH with blood led increased CSF [K+] and triggered cytosolic calcium activity ChP epithelial cells, which was followed by NKCC1 activation. ChP-targeted adeno-associated viral (AAV)-NKCC1 prevented blood-induced ventriculomegaly persistently clearance capacity. These data demonstrate trans-choroidal, NKCC1-dependent mechanism. Inactive, phosphodeficient AAV-NKCC1-NT51 failed ventriculomegaly. Excessive fluctuations correlated permanent shunting outcome humans hemorrhagic stroke, suggesting targeted gene therapy as potential treatment intracranial hemorrhage.

Language: Английский

Citations

41
Network state transitions during cortical development DOI
M. Wu, Nazim Kourdougli, Carlos Portera‐Cailliau

et al.

Nature reviews. Neuroscience, Journal Year: 2024, Volume and Issue: 25(8), P. 535 - 552

Published: May 23, 2024

Language: Английский

Citations

16
Dysregulation of Ion Channels and Transporters and Blood-Brain Barrier Dysfunction in Alzheimer’s Disease and Vascular Dementia DOI Creative Commons
Ruijia Liu,

Jenelle M Collier,

Nana-Hawwa Abdul-Rahman

et al.

Aging and Disease, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

The blood-brain barrier (BBB) plays a critical role in maintaining ion and fluid homeostasis, essential for brain metabolism neuronal function. Regulation of nutrient, water, transport across the BBB is tightly controlled by specialized transporters channels located within its unique cellular components. These dynamic processes not only influence BBB’s structure but also impact vital signaling mechanisms, optimal Disruption ion, pH, balance at associated with pathology has been implicated various neurological conditions, including stroke, epilepsy, trauma, neurodegenerative diseases such as Alzheimer’s disease (AD). However, knowledge gaps exist regarding dysregulation on function dementias. Several factors contribute to this gap: complex nature these historical research focus mechanisms technical challenges studying in vivo models lack efficient vitro dementia models. This review provides an overview current roles poses specific questions: 1) How are expression activity key altered AD vascular (VaD); 2) Do changes dysfunction progression; 3) Can restoring mitigate improve clinical outcomes. Addressing will provide greater insight into disorders.

Language: Английский

Citations

9
SPAK inhibitor ZT‐1a attenuates reactive astrogliosis and oligodendrocyte degeneration in a mouse model of vascular dementia DOI Creative Commons
Mohammad Iqbal H. Bhuiyan, Khadija Habib, Md. Tipu Sultan

et al.

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(3)

Published: March 1, 2024

Abstract Background Astrogliosis and white matter lesions (WML) are key characteristics of vascular contributions to cognitive impairment dementia (VCID). However, the molecular mechanisms underlying VCID remain poorly understood. Stimulation Na‐K‐Cl cotransport 1 (NKCC1) its upstream kinases WNK (with no lysine) SPAK (the STE20/SPS1‐related proline/alanine‐rich kinase) play a role in astrocytic intracellular Na + overload, hypertrophy, swelling. Therefore, this study, we assessed effect inhibitor ZT‐1a on pathogenesis function mouse model induced by bilateral carotid artery stenosis (BCAS). Methods Following sham or BCAS surgery, mice were randomly assigned receive either vehicle (DMSO) treatment regimen (days 14–35 post‐surgery). Mice then evaluated for functions Morris water maze, WML ex vivo MRI‐DTI analysis, astrogliosis/demyelination immunofluorescence immunoblotting. Results Compared control mice, BCAS‐Veh exhibited chronic cerebral hypoperfusion memory impairments, accompanied significant MRI DTI‐detected oligodendrocyte (OL) death. Increased activation WNK‐SPAK‐NKCC1‐signaling proteins was detected tissues C3d GFAP cytotoxic astrocytes but not S100A10 homeostatic mice. In contrast, ZT‐1a‐treated displayed reduced expression phosphorylation NKCC1, decreased astrogliosis, OL death, WML, along with improved functions. Conclusion BCAS‐induced upregulation WNK‐SPAK‐NKCC1 signaling contributes matter‐reactive impairment. Pharmacological inhibition activity has therapeutic potential alleviating VCID.

Language: Английский

Citations

7
GABAergic circuits drive focal seizures DOI Creative Commons
Elena Dossi, Gilles Huberfeld

Neurobiology of Disease, Journal Year: 2023, Volume and Issue: 180, P. 106102 - 106102

Published: March 26, 2023

Epilepsy is based on abnormal neuronal activities that have historically been suggested to arise from an excess of excitation and a defect inhibition, or in other words excessive glutamatergic drive not balanced by GABAergic activity. More recent data however indicate signaling defective at focal seizure onset may even be actively involved generation providing excitatory inputs. Recordings interneurons revealed they are active initiation their selective time-controlled activation using optogenetics triggers seizures more general context increased excitability. Moreover, appears mandatory many models. The main pro-ictogenic effect the depolarizing action GABAA conductance which occur when activity causes Cl- accumulation neurons. This process combine with background dysregulation Cl-, well described epileptic tissues. equilibrium maintained (Na+)/K+/Cl- co-transporters, can therefore favor effects GABA. In addition, these co-transporters further contribute this as mediate K+ outflow together extrusion, responsible for extracellular space subsequent increase local role obvious but its complex dynamics balance between flux polarity excitability still remain established, especially tissues where receptors ion regulators disrupted rather plays 2 faces Janus role.

Language: Английский

Citations

15
The NKCC1 inhibitor bumetanide restores cortical feedforward inhibition and lessens sensory hypersensitivity in early postnatal fragile X mice. DOI
Nazim Kourdougli,

Toshihiro Nomura,

M. Wu

et al.

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

Published: June 1, 2024

Language: Английский

Citations

6
Evaluation of bumetanide as a potential therapeutic agent for Alzheimer’s disease DOI Creative Commons

Ben Boyarko,

Sonia Podvin,

Barry Greenberg

et al.

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

Published: Aug. 4, 2023

Therapeutics discovery and development for Alzheimer’s disease (AD) has been an area of intense research to alleviate memory loss the underlying pathogenic processes. Recent drug approaches have utilized in silico computational strategies candidate selection which opened door repurposing drugs AD. Computational analysis gene expression signatures patients stratified by APOE4 risk allele AD led FDA-approved bumetanide as a top agent that reverses transcriptomic brain improves deficits animal models Bumetanide is loop diuretic inhibits kidney Na + -K -2Cl − cotransporter isoform, NKCC2, treatment hypertension edema cardiovascular, liver, renal disease. Electronic health record data revealed exposed lower incidences 35%–70%. In brain, proposed antagonize NKCC1 isoform mediates cellular uptake chloride ions. Blocking neuronal leads decrease intracellular thus promotes GABAergic receptor mediated hyperpolarization, may ameliorate conditions associated with GABAergic-mediated depolarization. expressed neurons all cells including glia (oligodendrocytes, microglia, astrocytes) vasculature. consideration repurposed AD, this review evaluates its pharmaceutical properties respect estimated levels across doses can improve neurologic distinguish between non-NKCC1 mechanisms. The available indicate efficacy occur at are below those required inhibition transporter implicates mechansims improvement dysfunctions deficits. Alternatively, peripheral mechanisms involve outside central nervous system (e.g., epithelia immune system). Clinical improved neurological reviewed. Regardless mechanism, model potential reduce incidence provide support clinical investigation therapeutic agent.

Language: Английский

Citations

12
Bidirectional Regulation of GABAA Reversal Potential in the Adult Brain: Physiological and Pathological Implications DOI Creative Commons
Haram Kim, Marco Martina

Life, Journal Year: 2024, Volume and Issue: 14(1), P. 143 - 143

Published: Jan. 19, 2024

In physiological conditions, the intracellular chloride concentration is much lower than extracellular. As GABAA channels are permeable to anions, reversal potential of very close that Cl−, which most abundant free anion in intra- and extracellular spaces. Intracellular regulated by activity ratio NKCC1 KCC2, two chloride-cation cotransporters import export respectively. Due closeness between value resting membrane neurons, small changes have a major functional impact, makes uniquely flexible signaling system. neurons adult brain, slightly more negative potential, hyperpolarizing. Alterations common feature numerous conditions as they consequence an imbalance NKCC1-KCC2 ratio. (including Alzheimer’s disease, schizophrenia, Down’s syndrome), becomes depolarizing, causes network desynchronization behavioral impairment. other (neonatal inflammation neuropathic pain), however, hypernegative, affects behavior through potent circuit deactivation.

Language: Английский

Citations

4