Haploinsufficiency of GABA<sub>A</sub>Receptor-Associated Clptm1 Enhances Phasic and Tonic Inhibitory Neurotransmission, Suppresses Excitatory Synaptic Plasticity, and Impairs Memory
Bibliographic record
Abstract
The mechanisms utilized by neurons to regulate the efficacy of phasic and tonic inhibition and their impacts on synaptic plasticity and behavior are incompletely understood. Cleft lip and palate transmembrane protein 1 (Clptm1) is a membrane-spanning protein that interacts with multiple γ-aminobutyric acid type A receptor (GABA A R) subunits, trapping them in the endoplasmic reticulum and Golgi network. Overexpression and knock-down studies suggest that Clptm1 modulates GABA A R-mediated phasic inhibition and tonic inhibition as well as activity-induced inhibitory synaptic homeostasis in cultured hippocampal neurons. To investigate the role of Clptm1 in the modulation of GABA A Rs in vivo, we generated Clptm1 knock-out (KO) mice. Here, we show that genetic KO of Clptm1 elevated phasic and tonic inhibitory transmission in both male and female heterozygous mice. Although basal excitatory synaptic transmission was not affected, Clptm1 haploinsufficiency significantly blocked high-frequency stimulation-induced long–term potentiation (LTP) in hippocampal CA3→CA1 synapses. In the hippocampus-dependent contextual fear-conditioning behavior task, both male and female Clptm1 heterozygous KO mice exhibited impairment in contextual fear memory. In addition, LTP and contextual fear memory were rescued by application of L-655,708, a negative allosteric modulator of the extrasynaptic GABA A R α5 subunit. These results suggest that haploinsufficiency of Clptm1 contributes to cognitive deficits through altered synaptic transmission and plasticity by elevation of inhibitory neurotransmission, with tonic inhibition playing a major role.
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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 | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".