Na<sup>+</sup>–Ca<sup>2+</sup>Exchanger (NCX3) Knock-Out Mice Display an Impairment in Hippocampal Long-Term Potentiation and Spatial Learning and Memory

Molinaro, Pasquale; Viggiano, D.; Nisticò, Robert; Sirabella, Rossana; Secondo, Agnese; Boscia, Francesca; Pannaccione, Anna; Scorziello, Antonella; Mehdawy, Bisan; Sokolow, Sophie; Herchuelz, André; Renzo, G. F. Di; Annunziato, Lucio

doi:10.1523/jneurosci.6296-10.2011

Cited by 77 publications

(68 citation statements)

References 38 publications

(41 reference statements)

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“…32 Interestingly, we have recently provided evidence that NCX3-knockout mice show an impairment in hippocampal LTP, spatial learning, and memory. 23 Overall, our findings, by providing new insights into the molecular and cellular mechanisms involved in OPC development, demonstrate for the first time that calcium signaling mediated by the NCX3 isoform is crucially involved in oligodendrocyte maturation and myelin formation. Further studies are nonetheless required to reveal whether alterations in NCX3 activity might contribute to OPC dysfunction in de-myelinating diseases, and whether its modulation might be therapeutically relevant.…”

Section: Discussionmentioning

confidence: 57%

“…To assess whether NCX3 might have a role in CNS myelination, we analyzed the expression of myelin markers in the oligodendrocytes of mice lacking NCX3, an animal model that has been extensively characterized in our laboratory as well as in others. 22,14,23 For instance, our previous western blot analyses in brain tissue homogenates from ncx3 þ / þ and ncx3 À/À mice have revealed no detectable NCX3 protein levels in ncx3-null mice. 14,23 Colocalization experiments, performed using the neuronal marker NeuN or the oligodendrocyte marker MBP in the presence of the NCX3 antibody, revealed that the NCX3 protein was expressed both in the gray and the white matter of the spinal cord of congenic, wild-type, ncx3 þ / þ mice ( Figure 8A).…”

Section: Resultsmentioning

confidence: 99%

“…22,14,23 For instance, our previous western blot analyses in brain tissue homogenates from ncx3 þ / þ and ncx3 À/À mice have revealed no detectable NCX3 protein levels in ncx3-null mice. 14,23 Colocalization experiments, performed using the neuronal marker NeuN or the oligodendrocyte marker MBP in the presence of the NCX3 antibody, revealed that the NCX3 protein was expressed both in the gray and the white matter of the spinal cord of congenic, wild-type, ncx3 þ / þ mice ( Figure 8A). Interestingly, spinal cords isolated from ncx3 À/À mice were smaller than those isolated from wild-type, congenic, ncx3 þ / þ mice ( Figure 8B).…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, we found that NCX3-knockout mice show hypo-myelination that is accompanied by an augmented expression of the OPC marker NG2 and a reduction of spinal cord size. NCX3 is most likely not critical for embryonic brain development as the gross cytoarchitecture of neurons, 23 astrocytes, and OPCs was not altered in ncx3 À/À mice. More specifically, the hypo-myelinization observed in the NCX3-knockout mice of the present study might be explained by evidence indicating that the formation of myelin is a protracted developmental process extending during the postnatal period.…”

Section: Discussionmentioning

confidence: 99%

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Silencing or knocking out the Na+/Ca2+ exchanger-3 (NCX3) impairs oligodendrocyte differentiation

et al. 2011

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Changes in intracellular [Ca 2 þ ] i levels have been shown to influence developmental processes that accompany the transition of human oligodendrocyte precursor cells (OPCs) into mature myelinating oligodendrocytes and are required for the initiation of the myelination and re-myelination processes. In the present study, we explored whether calcium signals mediated by the selective sodium calcium exchanger (NCX) family members NCX1, NCX2, and NCX3, play a role in oligodendrocyte maturation. Functional studies, as well as mRNA and protein expression analyses, revealed that NCX1 and NCX3, but not NCX2, were divergently modulated during OPC differentiation into oligodendrocyte phenotype. In fact, whereas NCX1 was downregulated, NCX3 was strongly upregulated during oligodendrocyte development. The importance of calcium signaling mediated by NCX3 during oligodendrocyte maturation was supported by several findings. Indeed, whereas knocking down the NCX3 isoform in OPCs prevented the upregulation of the myelin protein markers 2 0 ,3 0 -cyclic nucleotide-3 0 -phosphodiesterase (CNPase) and myelin basic protein (MBP), its overexpression induced an upregulation of CNPase and MBP. Furthermore, NCX3-knockout mice showed not only a reduced size of spinal cord but also marked hypo-myelination, as revealed by decrease in MBP expression and by an accompanying increase in OPC number. Collectively, our findings indicate that calcium signaling mediated by NCX3 has a crucial role in oligodendrocyte maturation and myelin formation. Oligodendrocytes, the myelin-forming cells of the CNS, arise from oligodendrocyte precursor cells (OPCs) that colonize both the gray and the white brain matter during development. 1 Although many OPCs differentiate into mature myelinating oligodendrocytes during the early and much later stages of human brain development, a considerable number of them do persist in the adult brain, and may provide a source of new oligodendrocytes, as well as protoplasmic astrocytes and neurons. 2,3 Because of their apparent stem-like characteristics, adult OPCs have recently gained much attention, for they are regarded as a potential reservoir of cells capable of self-renewal, differentiation, and re-myelination after CNS injury. 4 Thus, understanding how oligodendrocyte development proceeds and what factors govern the differentiation fate of OPCs is crucial to discover new effective therapeutic targets for de-myelinating diseases such as multiple sclerosis (MS).Changes in intracellular calcium levels have a critical role in OPC migration, lineage progression, and differentiation; furthermore, they are required for myelination and remyelination processes. [5][6][7] The Na þ /Ca 2 þ exchanger (NCX), 8 a transmembrane domain protein, which, by operating in a bidirectional way, couples the efflux of Ca 2 þ to the influx of Na þ into the cell or, vice versa, the influx of Ca 2 þ to the efflux of Na þ , is involved in the regulation of diverse neuronal and glial cell functions. 8,9 Furthermore, NCX is involved in regulating int...

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Section: Discussionmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Silencing or knocking out the Na+/Ca2+ exchanger-3 (NCX3) impairs oligodendrocyte differentiation

et al. 2011

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“…Clearly, since the extracellular proteins can bind both calcium and Na + , some extrarenal form of interaction between the two ions might exist. For instance, it is well known that Unauthenticated Download Date | 5/11/18 1:00 PM many cells express a Na + -Ca +2 Exchanger (NCX), and that there is a perfect coupling between Na + and calcium transcellular fluxes based on their extracellular concentrations [6,7]. The exact knowledge of this interplay is important because it may provide an additional mechanism of sodium regulation, independent of the kidney function; in addition, this regulation might have clinical impact particularly in patients undergoing dialysis (who lack kidney regulation for extracellular sodium and rely on the dialysis system).…”

Section: Introductionmentioning

confidence: 99%

Plasma Calcium Concentration Modifies the Blood Sodium During Hemodialysis: Lessons from Hard Water Syndrome

Viggiano

Anastasio

2017

BANTAO Journal

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Introduction. Extracellular sodium (Na + ) concentration is maintained within a tight physiological range due to hormonal control, that mainly modulates thirst, Na + and water renal excretion. Extra-renal regulation of Na + and water homeostasis is only partially understood. Recently it has been debated whether the osmotically inactive Na + storage is fixed or variable. Methods. In the present study, fourteen End-Stage Renal Disease (ESRD) patients treated by chronic hemodialysis underwent by accident to a sharp increase in plasmatic calcium (Ca +2 ) levels due to the failure of the water control system, leading to the so-called hard water syndrome. The levels of plasmatic Ca +2 after 1 hr of hemodialysis were correlated with urea, Na + , potassium (K + ) and creatinine levels. Eleven ESRD patients treated with hemodialysis under similar conditions were used as controls. Results. The hard water syndrome resulted in hypercalcemia, while mean plasma levels of Na + , K + and urea were not different compared to controls. Plasma creatinine levels were slightly but significantly higher that control. A correlation analysis on the measured variables has showed a positive correlation between plasma Ca +2 and Na + levels (Pearson=0.428, p=0.032), and the absence of any correlation with K + , creatinine and urea concentration. Conclusions. Our study suggests that acute changes in plasmatic Ca +2 levels may affect Na + concentration in the absence of renal function; it is possible that hypercalcemia may trigger Na + release from the osmotically inactive storage. These data further support previous observations on the interplay of sodium and calcium at extrarenal sites.

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Recent structural and functional insights into the family of sodium calcium exchangers

Sharma

O'Halloran

2013

Genesis

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Maintenance of calcium homeostasis is necessary for the development and survival of all animals. Calcium ions modulate excitability and bind effectors capable of initiating many processes such as muscular contraction and neurotransmission. However, excessive amounts of calcium in the cytosol or within intracellular calcium stores can trigger apoptotic pathways in cells that have been implicated in cardiac and neuronal pathologies. Accordingly, it is critical for cells to rapidly and effectively regulate calcium levels. The Na(+) /Ca(2+) exchangers (NCX), Na(+) /Ca(2+) /K(+) exchangers (NCKX), and Ca(2+) /Cation exchangers (CCX) are the three classes of sodium calcium antiporters found in animals. These exchanger proteins utilize an electrochemical gradient to extrude calcium. Although they have been studied for decades, much is still unknown about these proteins. In this review, we examine current knowledge about the structure, function, and physiology and also discuss their implication in various developmental disorders. Finally, we highlight recent data characterizing the family of sodium calcium exchangers in the model system, Caenorhabditis elegans, and propose that C. elegans may be an ideal model to complement other systems and help fill gaps in our knowledge of sodium calcium exchange biology.

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Na⁺–Ca²⁺Exchanger (NCX3) Knock-Out Mice Display an Impairment in Hippocampal Long-Term Potentiation and Spatial Learning and Memory

Cited by 77 publications

References 38 publications

Silencing or knocking out the Na+/Ca2+ exchanger-3 (NCX3) impairs oligodendrocyte differentiation

Silencing or knocking out the Na+/Ca2+ exchanger-3 (NCX3) impairs oligodendrocyte differentiation

Plasma Calcium Concentration Modifies the Blood Sodium During Hemodialysis: Lessons from Hard Water Syndrome

Recent structural and functional insights into the family of sodium calcium exchangers

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Na+–Ca2+Exchanger (NCX3) Knock-Out Mice Display an Impairment in Hippocampal Long-Term Potentiation and Spatial Learning and Memory

Cited by 77 publications

References 38 publications

Silencing or knocking out the Na+/Ca2+ exchanger-3 (NCX3) impairs oligodendrocyte differentiation

Silencing or knocking out the Na+/Ca2+ exchanger-3 (NCX3) impairs oligodendrocyte differentiation

Plasma Calcium Concentration Modifies the Blood Sodium During Hemodialysis: Lessons from Hard Water Syndrome

Recent structural and functional insights into the family of sodium calcium exchangers

Contact Info

Product

Resources

About

Na⁺–Ca²⁺Exchanger (NCX3) Knock-Out Mice Display an Impairment in Hippocampal Long-Term Potentiation and Spatial Learning and Memory