Cortical cells reveal APP as a regulator of GABAergic neurotransmission

Doshina, Anna; Gourgue, Florian; Onizuka, Michiho; Opsomer, Reinier-Jacques; Wang, Peng; Ando, Kunie; Tasiaux, Bernadette; Dewachter, Ilse; Kienlen‐Campard, Pascal; Brion, Jean Pierre; Gailly, Philippe; Octave, Jean Noël; Pierrot, Nathalie

doi:10.3389/conf.fnins.2017.94.00114

Cited by 2 publications

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“…In numerous pathophysiological conditions such as epilepsy, TBI, and stroke, the dedifferentiation of neurons is associated with a marked increase in NKCC1 expression accompanied by downregulation of KCC2 thus recapitulating the expression profiles found in immature neurons (Payne et al, 2003;Jaenisch et al, 2010;Kharod et al, 2019). With respect to AD, Aβ42 increases NKCC1 in mouse hippocampus (Lam et al, 2022), and APP expression decreases KCC2 in cortical cells without modifying NKCC1 (Doshina et al, 2017). Such research suggests that elevated NKCC1 with diminished KCC2 may predict an altered balance of excitatory to inhibitory (E/I) activity towards excitatory GABAergic signaling.…”

Section: Figurementioning

confidence: 78%

Evaluation of bumetanide as a potential therapeutic agent for Alzheimer’s disease

et al. 2023

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

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Section: Figurementioning

confidence: 78%

Evaluation of bumetanide as a potential therapeutic agent for Alzheimer’s disease

et al. 2023

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“…In addition, it was shown that reducing KCC2 activity in the hippocampus was sufficient to induce temporal lobe epilepsy in mice (Kelley et al, 2018). KCC2 function could also be impaired in pain (Mapplebeck et al, 2019), schizophrenia (Arion and Lewis, 2011), Alzheimer's disease (Doshina et al, 2017;Bie et al, 2022), and autism (Merner et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Conditional deletion of KCC2 impairs synaptic plasticity and both spatial and nonspatial memory

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Yerna

et al. 2023

Front. Mol. Neurosci.

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The postsynaptic inhibition through GABAA receptors (GABAAR) relies on two mechanisms, a shunting effect due to an increase in the postsynaptic membrane conductance and, in mature neurons, a hyperpolarization effect due to an entry of chloride into postsynaptic neurons. The second effect requires the action of the K+–Cl− cotransporter KCC2 which extrudes Cl− from the cell and maintains its cytosolic concentration very low. Neuronal chloride equilibrium seems to be dysregulated in several neurological and psychiatric conditions such as epilepsy, anxiety, schizophrenia, Down syndrome, or Alzheimer’s disease. In the present study, we used the KCC2 Cre-lox knockdown system to investigate the role of KCC2 in synaptic plasticity and memory formation in adult mice. Tamoxifen-induced conditional deletion of KCC2 in glutamatergic neurons of the forebrain was performed at 3 months of age and resulted in spatial and nonspatial learning impairment. On brain slices, the stimulation of Schaffer collaterals by a theta burst induced long-term potentiation (LTP). The lack of KCC2 did not affect potentiation of field excitatory postsynaptic potentials (fEPSP) measured in the stratum radiatum (dendrites) but increased population spike (PS) amplitudes measured in the CA1 somatic layer, suggesting a reinforcement of the EPSP-PS potentiation, i.e., an increased ability of EPSPs to generate action potentials. At the cellular level, KCC2 deletion induced a positive shift in the reversal potential of GABAAR-driven Cl− currents (EGABA), suggesting an intracellular accumulation of chloride subsequent to the downregulation of KCC2. After treatment with bumetanide, an antagonist of the Na+-K+-Cl− cotransporter NKCC1, spatial memory impairment, chloride accumulation, and EPSP-PS potentiation were rescued in mice lacking KCC2. The presented results emphasize the importance of chloride equilibrium and GABA-inhibiting ability in synaptic plasticity and memory formation.

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Cortical cells reveal APP as a regulator of GABAergic neurotransmission

Cited by 2 publications

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Evaluation of bumetanide as a potential therapeutic agent for Alzheimer’s disease

Evaluation of bumetanide as a potential therapeutic agent for Alzheimer’s disease

Conditional deletion of KCC2 impairs synaptic plasticity and both spatial and nonspatial memory

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