Multiprotein complexes regulating excitatory and inhibitory neurotransmission in the brain
Bibliographic record
Abstract
It is now firmly established that imbalances between neuronal excitation (E) and inhibition (I) commonly manifest in neurological and neuropsychiatric disorders 1,2 . However, the precise molecular machinery that underlies E:I balance regulation in neurons is poorly understood. KCC2 is the only neuron‐specific K + Cl − cotransporter that extrudes Cl‐from mature neurons, enabling them to maintain a low intracellular [Cl − ], essential for fast inhibitory neurotransmission 3,4 . Additionally, KCC2 plays important roles in excitatory neurotransmission by regulating dendritic spine morphogenesis 3 . KCC2 dysfunction contributes to human neurological disorders including, epilepsy, neuropathic pain and multiple neuropsychiatric disorders 5–10 . Since KCC2 is at the crux of both synaptic excitation and inhibition and is implicated in neurological disorders, it is imperative to identify the full‐range of KCC2 binding partners to have a firm grasp of its biology. First, using a candidate approach, we made a surprising discovery that native KCC2 exists in a physical and functional complex with native‐ionotropic glutamate receptor (iGluR) subunit GluK2 11 , and its auxiliary subunit Neto2 12,13 in hippocampal neurons; and that they regulate KCC2‐mediated neuronal Cl − homeostasis. In the present abstract, we reveal that native KCC2 coexists with several members of recycling machinery at the post synapse that have been established to regulate iGluR recycling and surface expression; and also regulate KCC2 cell biology and function. Overall, we identify the existence of members of synaptic inhibition and synaptic excitation within the same macromolecular complex, creating a framework for (i) understanding the fundamental nexus between cell‐intrinsic synaptic excitation and inhibition, and (ii) provide novel therapeutic strategies to rescue KCC2 deficits that occur in E:I imbalance disorders of the nervous system. Support or Funding Information CIHR
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".