A Novel Small Molecule Targets NKCC1 To Restore Synaptic Inhibition

Raveendran, Vineeth A.; Pressey, Jessica C.; Woodin, Melanie A.

doi:10.1016/j.tips.2020.10.002

Cited by 7 publications

(3 citation statements)

References 10 publications

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“…In various studies, targeting the GABAergic circuit has improved synaptic and behavioural deficits observed in the murine models of neurodevelopmental disorders (Banerjee et al 2016;Deidda, Parrini, et al 2015;He et al 2019;Braat and Kooy 2015;Cellot and Cherubini 2014;Savardi et al 2020;D'Hulst and Kooy 2007;Raveendran, Pressey, and Woodin 2020) and, thus, we speculated that restoring GABAergic function to WT levels can correct behavioural deficits in Syngap1 +/mice. Our initial findings described the altered function of Chloride co-transporters (reversal potential of GABA) at P14-15 was restored when 6BIO was administered in Syngap1 +/mice.…”

Section: Discussionmentioning

confidence: 91%

Reversing GABA polarity corrects synaptic physiology and behavioural deficits in young adolescent Syngap1+/- mice

Verma

Kumar

Sharma

et al. 2021

Preprint

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Haploinsufficiency in SYNGAP1 is implicated in Intellectual Disability (ID) and Autism Spectrum disorder (ASD) and affects the maturation of dendritic spines. The abnormal spine development has been suggested to cause disbalance of excitatory and inhibitory (E/I) neurotransmission at distinct developmental periods. In addition, E/I imbalances in Syngap1+/- mice might be due to abnormalities in K+-Cl- co-transporter function (NKCC1, KCC2), in a similar manner as in the murine models of Fragile-X and Rett syndromes. To study whether an altered intracellular chloride ion concentration represents an underlying mechanism of altered function of GABAergic synapses in Dentate Gyrus Granule Cells of Syngap1+/- recordings were performed at different developmental stages of the mice. We observed that neurons at P14-15 of Syngap1+/- mice had depolarised membrane potential and a decreased Cl- reversal potential. The KCC2 expression was decreased compared to Wild-type (WT) mice at P14-15. Furtherly, the small molecule GSK-3β inhibitor, 6-bromoindirubin-3`-oxime (6BIO), was tested in an attempt to restore the function of GABAergic synapses. We discovered that intraperitoneal administration of 6BIO during the critical period or young adolescents normalized an altered E/I balance, the deficits of synaptic transmission, and behavioral performance like social novelty, anxiety, and memory of the Syngap1+/- mice. In summary, altered functionality of GABAergic synapses in Syngap1+/- mice is based on a reduced KCC2 expression and a subsequent increase in the intracellular chloride concentration that can be counteracted by the small molecule 6BIO. The 6BIO sufficiently restored cognitive, emotional, and social symptoms by pharmacological intervention, particularly, in adulthood.

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Section: Discussionmentioning

confidence: 91%

Reversing GABA polarity corrects synaptic physiology and behavioural deficits in young adolescent Syngap1+/- mice

Verma

Kumar

Sharma

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…However, in individuals with DS, GABA acts in an opposite, excitatory manner: instead of reducing the flow, it stimulates it, making it excessive and unregulated due to the imbalance of an electrolyte, the chloride ion (Ben-Ari, 2002 ; Contestabile et al, 2017 ). Pharmacological interventions with drugs targeting Cl − homeostasis, such as inhibiting Na–K–Cl cotransporter (NKCC1) and/or activating Potassium chloride cotransporter-2 (KCC2), might restore E/I imbalance resulting from an impaired Cl–gradient (Raveendran et al, 2020 ; Savardi et al, 2023 ) and rescue cognitive impairment in DS mouse models (Contestabile et al, 2017 ).…”

Section: Hypothesis Of Tdcs Treatment Application In Down Syndromementioning

confidence: 99%

Transcranial Direct Current Stimulation in neurogenetic syndromes: new treatment perspectives for Down syndrome?

Faralli,

Fucà,

Lazzaro

et al. 2024

Front. Cell. Neurosci.

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This perspective review aims to explore the potential neurobiological mechanisms involved in the application of transcranial Direct Current Stimulation (tDCS) for Down syndrome (DS), the leading cause of genetically-based intellectual disability. The neural mechanisms underlying tDCS interventions in genetic disorders, typically characterized by cognitive deficits, are grounded in the concept of brain plasticity. We initially present the neurobiological and functional effects elicited by tDCS applications in enhancing neuroplasticity and in regulating the excitatory/inhibitory balance, both associated with cognitive improvement in the general population. The review begins with evidence on tDCS applications in five neurogenetic disorders, including Rett, Prader-Willi, Phelan-McDermid, and Neurofibromatosis 1 syndromes, as well as DS. Available evidence supports tDCS as a potential intervention tool and underscores the importance of advancing neurobiological research into the mechanisms of tDCS action in these conditions. We then discuss the potential of tDCS as a promising non-invasive strategy to mitigate deficits in plasticity and promote fine-tuning of the excitatory/inhibitory balance in DS, exploring implications for cognitive treatment perspectives in this population.

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“…In addition, ARN23746 had an improved pharmacokinetic profile in vivo, rescued cognitive deficits in Ts65Dn mice, and had no significant diuretic effect in wild-type or DS mice compared with bumetanide [ 120 ] ( Table 1 ). However, Raveendran and colleagues gave a word of caution with selectively targeting NKCC1, as it is ubiquitously expressed, and chronic treatment with NKCC1 inhibitors such as bumetanide can lead to ototoxicity in the inner ear [ 126 , 127 , 128 ]. A recent study also suggested bumetanide is neurotoxic even at low micromolar concentrations as primary hippocampal mouse neurons had greater cell death with bumetanide than Aβ 1–42 alone [ 63 ].…”

Section: Pharmacological Targeting Of the Cation-chloride Cotransportersmentioning

confidence: 99%

Cation-Chloride Cotransporters KCC2 and NKCC1 as Therapeutic Targets in Neurological and Neuropsychiatric Disorders

et al. 2023

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Neurological diseases including Alzheimer’s, Huntington’s disease, Parkinson’s disease, Down syndrome and epilepsy, and neuropsychiatric disorders such as schizophrenia, are conditions that affect not only individuals but societies on a global scale. Current therapies offer a means for small symptomatic relief, but recently there has been increasing demand for therapeutic alternatives. The γ-aminobutyric acid (GABA)ergic signaling system has been investigated for developing new therapies as it has been noted that any dysfunction or changes to this system can contribute to disease progression. Expression of the K-Cl-2 (KCC2) and N-K-C1-1 (NKCC1) cation-chloride cotransporters (CCCs) has recently been linked to the disruption of GABAergic activity by affecting the polarity of GABAA receptor signaling. KCC2 and NKCC1 play a part in multiple neurological and neuropsychiatric disorders, making them a target of interest for potential therapies. This review explores current research suggesting the pathophysiological role and therapeutic importance of KCC2 and NKCC1 in neuropsychiatric and neurological disorders.

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A Novel Small Molecule Targets NKCC1 To Restore Synaptic Inhibition

Cited by 7 publications

References 10 publications

Reversing GABA polarity corrects synaptic physiology and behavioural deficits in young adolescent Syngap1+/- mice

Reversing GABA polarity corrects synaptic physiology and behavioural deficits in young adolescent Syngap1+/- mice

Transcranial Direct Current Stimulation in neurogenetic syndromes: new treatment perspectives for Down syndrome?

Cation-Chloride Cotransporters KCC2 and NKCC1 as Therapeutic Targets in Neurological and Neuropsychiatric Disorders

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