Ion Transporter NKCC1, Modulator of Neurogenesis in Murine Olfactory Neurons

Haering, Claudia; Kanageswaran, Ninthujah; Bouvain, Pascal; Scholz, Paul; Altmüller, Janine; Becker, Christian; Gisselmann, Günter; Wäring-Bischof, Janine; Hatt, Hanns

doi:10.1074/jbc.m115.640656

Cited by 18 publications

(9 citation statements)

References 68 publications

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“…AE2 and/or other HCO 3 - dependent mechanisms contribute to Cl - regulation, and thus could be compensating for the loss of NKCC1 in GnRH neurons. Consistent with this hypothesis, Haering et al recently reported increases in transcript for three Cl - transporters including AE2 (Slc4a2), in the olfactory epithelium of NKCC1 -/- mice [ 41 ].…”

Section: Discussionmentioning

confidence: 84%

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Chloride Accumulators NKCC1 and AE2 in Mouse GnRH Neurons: Implications for GABAA Mediated Excitation

2015

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A developmental “switch” in chloride transporters occurs in most neurons resulting in GABAA mediated hyperpolarization in the adult. However, several neuronal cell subtypes maintain primarily depolarizing responses to GABAA receptor activation. Among this group are gonadotropin-releasing hormone-1 (GnRH) neurons, which control puberty and reproduction. NKCC1 is the primary chloride accumulator in neurons, expressed at high levels early in development and contributes to depolarization after GABAA receptor activation. In contrast, KCC2 is the primary chloride extruder in neurons, expressed at high levels in the adult and contributes to hyperpolarization after GABAA receptor activation. Anion exchangers (AEs) are also potential modulators of responses to GABAA activation since they accumulate chloride and extrude bicarbonate. To evaluate the mechanism(s) underlying GABAA mediated depolarization, GnRH neurons were analyzed for 1) expression of chloride transporters and AEs in embryonic, pre-pubertal, and adult mice 2) responses to GABAA receptor activation in NKCC1-/- mice and 3) function of AEs in these responses. At all ages, GnRH neurons were immunopositive for NKCC1 and AE2 but not KCC2 or AE3. Using explants, calcium imaging and gramicidin perforated patch clamp techniques we found that GnRH neurons from NKCC1-/- mice retained relatively normal responses to the GABAA agonist muscimol. However, acute pharmacological inhibition of NKCC1 with bumetanide eliminated the depolarization/calcium response to muscimol in 40% of GnRH neurons from WT mice. In the remaining GnRH neurons, HCO3 - mediated mechanisms accounted for the remaining calcium responses to muscimol. Collectively these data reveal mechanisms responsible for maintaining depolarizing GABAA mediated transmission in GnRH neurons.

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Section: Discussionmentioning

confidence: 84%

“…Previous research has shown that tissue from NKCC1 -/- mice show compensatory changes for the loss of NKCC1 [ 40 , 41 ]. Therefore we measured the MUS response in NIH Swiss WT mice (“WT”), either with or without the NKCC1 inhibitor Bumetanide (BUME).…”

Section: Resultsmentioning

confidence: 99%

Chloride Accumulators NKCC1 and AE2 in Mouse GnRH Neurons: Implications for GABAA Mediated Excitation

2015

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“…These might be caused by the reduction of cell number, and thickness of the neuronal layer in the MOE of AC3 −/− mice as revealed in many olfactory related gene knockout mice. For example, a decrease of 20% was revealed in both thickness and cell number in the MOE of NKCC1-deficient mice [ 46 ]. In the ATF5 knockout (KO) MOEs, the numbers of OR-expressing neurons are significantly reduced [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiles of Main Olfactory Epithelium in Adenylyl Cyclase 3 Knockout Mice

Wang

Zhou

Luo

et al. 2015

IJMS

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Adenylyl Cyclase 3 (AC3) plays an important role in the olfactory sensation-signaling pathway in mice. AC3 deficiency leads to defects in olfaction. However, it is still unknown whether AC3 deficiency affects gene expression or olfactory signal transduction pathways within the main olfactory epithelium (MOE). In this study, gene microarrays were used to screen differentially expressed genes in MOE from AC3 knockout (AC3−/−) and wild-type (AC3+/+) mice. The differentially expressed genes identified were subjected to bioinformatic analysis and verified by qRT-PCR. Gene expression in the MOE from AC3−/− mice was significantly altered, compared to AC3+/+ mice. Of the 41266 gene probes, 3379 had greater than 2-fold fold change in expression levels between AC3−/− and AC3+/+ mice, accounting for 8% of the total gene probes. Of these genes, 1391 were up regulated, and 1988 were down regulated, including 425 olfactory receptor genes, 99 genes that are specifically expressed in the immature olfactory neurons, 305 genes that are specifically expressed in the mature olfactory neurons, and 155 genes that are involved in epigenetic regulation. Quantitative RT-PCR verification of the differentially expressed epigenetic regulation related genes, olfactory receptors, ion transporter related genes, neuron development and differentiation related genes, lipid metabolism and membrane protein transport etc. related genes showed that P75NTR, Hinfp, Gadd45b, and Tet3 were significantly up-regulated, while Olfr370, Olfr1414, Olfr1208, Golf, Faim2, Tsg101, Mapk10, Actl6b, H2BE, ATF5, Kirrrel2, OMP, Drd2 etc. were significantly down-regulated. In summary, AC3 may play a role in proximal olfactory signaling and play a role in the regulation of differentially expressed genes in mouse MOE.

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“…A mixture of 89 molecules was Mixture C (Henkel 100 #13‐11,845; n = 100) containing odorants of different classes and groups, including aromatics, aliphatics, alcohols, aldehydes, esters, ethers, ketones, amines, alkanes, heterocyclics, etc. This mixture of odorants and subdivisions of a smaller number of components have been previously used in studies examining the specificity and sensitivity of human ORs (Wetzel et al, ) and olfactory epithelium signaling (Haering et al, ; Wetzel, Brunert, & Hatt, ). In the current study, we expanded the perspective on Henkel100 by looking at its olfactory thresholds.…”

Section: Methodsmentioning

confidence: 99%

Molecularly diverse odors advance olfactory threshold testing

Oleszkiewicz

Würfel

Han

et al. 2018

Journal of Sensory Studies

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Multiple‐compound mixtures of odorants are likely to produce significantly more reliable and favorable results of olfactory sensitivity testing. Within the current study, we aimed to investigate this hypothesis and determine the optimal number of odor compounds within a testing stimulus. One‐hundred individuals volunteered to participate in the study procedure wherein their olfactory threshold was measured with stimuli varying in the number of compounds during two sessions. We found that molecularly varied stimuli made olfactory threshold assessments relatively independent from an individual variability in sensitivity to specific odorants. Nevertheless, this was only true in certain conditions—depending on the number of components and quality of the odorants. On this basis, we outline future directions for studies aimed to advance assessments of the olfactory threshold by discussing the relationships between the chemical and physical properties of odorants and results of the threshold assessment they produce. Practical applications This study provides empirical evidence that olfactory threshold testing becomes more favorable and reliable when an odor stimulus contains ~10 types of molecules. This is assumed due to an efficient activation of olfactory receptors. These findings advance the current state of knowledge in the field of biology by presenting behavioral responses to the augmented potential for binding molecules through olfactory receptors. Results presented in this manuscript constitute a significant improvement in the methods of olfactory function assessments and should be of interest to both scientific and clinical audience in the fields of neuroscience, chemosensory research, chemistry, and biology. These results are likely to translate to a more accurate assessment of olfactory abilities in commercial settings, that is, perfumes, or wine experts.

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Ion Transporter NKCC1, Modulator of Neurogenesis in Murine Olfactory Neurons

Cited by 18 publications

References 68 publications

Chloride Accumulators NKCC1 and AE2 in Mouse GnRH Neurons: Implications for GABAA Mediated Excitation

Chloride Accumulators NKCC1 and AE2 in Mouse GnRH Neurons: Implications for GABAA Mediated Excitation

Gene Expression Profiles of Main Olfactory Epithelium in Adenylyl Cyclase 3 Knockout Mice

Molecularly diverse odors advance olfactory threshold testing

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