| Outcome (primary/secondary) |
Model/study |
Direction of effect |
Mechanistic insight |
Evidence type/certainty |
| Cognitive flexibility/reversal learning |
Kcnt1 null mice [11] |
Impaired |
Slack channels required for adapting to new situations; regulates anxiety-like behavior |
Experimental, animal/moderate |
| Spatial learning/reference memory |
Kcnt1 -/- mice [12] |
No defect |
Kcnt1 deletion protects from seizures; adult models may not represent infancy-onset disease |
Experimental, animal/low-moderate |
| Working memory |
Rat PFC neurons [15] |
Improved with HCN-Slack blockade |
HCN-Slack complex suppresses neuronal excitability; links channel function to working memory |
Experimental, animal/moderate |
| FMRP translation/protein synthesis |
HEK cells, primary neurons [16] |
Increased translation with Slack activation |
Slack-FMRP/CYFIP1 dissociation promotes mRNA translation; affects β-actin synthesis |
Experimental, cell/moderate |
| FMRP and Slack interaction |
Aplysia neurons, xenopus oocytes [6] |
FMRP enhances Slack activity |
Interaction may link neuronal firing to protein translation, influencing excitability |
Experimental, cell/low |
| ID linked to epilepsy/Slack channels |
Systematic review [9] |
Association reported |
Slack channels linked to cognitive delays in early-onset epileptic encephalopathies |
Systematic review, AMSTAR 2/critically low |
| Potassium channelopathies and ID |
Systematic review [13] |
Gain-/loss-of-function mutations lead to ID |
Mechanisms not fully understood; 19 channelopathies identified |
Systematic review, AMSTAR 2/low |
| Human genotype-phenotype (KCNT2 variants) |
Case report [14] |
ID + seizures |
Gain/loss mutations affect excitability; quinidine as potential therapy |
Case report/very low |
