Sex Differences in the Chloride Cotransporters, NKCC1 and KCC2, in the Developing Hypothalamus
Bibliographic record
Abstract
In immature neurones, high basal [Cl(-)](i) results in membrane depolarisation following GABA(A) receptor activation, which is critical for various developmental processes including steroid-mediated sexual differentiation of the hypothalamus. Previously, we demonstrated that oestradiol enhances GABA-mediated Ca(2+) influx in neonate hypothalamus and that Ca(2+) induced activation of the transcription factor, cyclicAMP response element binding protein (CREB), was higher in male (high oestradiol) relative to female neonate hypothalamus. Based on these results, we hypothesised that expression of developmentally regulated chloride cotransporters may be sexually dimorphic. Here, we investigate the expression of the chloride cotransporters, NKCC1 (Na-K-2Cl(-)) and KCC2 (K-Cl(-)) in neonate mediobasal hypothalamus of male and female rats. The NKCC1 transporter moves Cl(-) into cells and helps maintain depolarising GABA action while the KCC2 transporter has the opposite effect by moving Cl(-) out of cells. NKCC1 mRNA levels were higher in males than females on the day of birth (postnatal day 0; PND 0) and total NKCC1 protein levels were significantly higher in males than females on embryonic day (ED) 20 and PND0. Levels of activated phosphorylated NKCC1 (pNKCC1) were not sexually dimorphic. Females were treated with a masculinising dose of oestradiol benzoate (EB; 100 microg; EB-females) on PND0. Total NKCC1 protein levels in tissue processed on PND1 and PND2 were similar in EB-females and oil-treated PND0 males and females. However, pNKCC1 protein levels measured on PND2 (but not PND1) were significantly higher in EB-treated females relative to oil-treated males and females. By contrast, KCC2 mRNA levels were significantly lower in males relative to females on PND0. KCC2 protein was not detectable on ED20 or PND0 but was significantly lower in males relative to females on PND5. These results suggest a complex relationship between KCC2 and NKCC1 mRNA and protein in developing brain that is not easily linked to regulation by oestradiol.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".