Table 3. Study characteristics.

This table summarizes the included studies: study type, model systems, methodologies, key results, and limitations and provides an overview of experimental studies, systematic reviews, and case reports investigating the role of Slo2/KCNT1/KCNT2 channels in intellectual disability and related neurodevelopmental disorders. It details the type of study, model system or population used, primary methodologies employed, main findings, and notable limitations for each study, highlighting strengths, potential biases, and gaps in the existing literature.

Study	Study type	Model system	Methodology	Results	Limitation
Zhang et al. (2012) [6]	Experimental study	Aplysia bag cell neurons, xenopus oocytes	Immunocytochemistry and coimmunoprecipitation to demonstrate FMRP and Slack interaction. RNA interference (siRNA) to suppress Slack expression. Cloning of Aplysia Slack using PCR from a cDNA library. Electrophysiological techniques. Intracellular injection of FMRP to observe effects on outward currents. Biphasic outward current measured	FMRP and Slack channels interact, and FMRP enhances Slack channel activity. The interaction may link neuronal firing to protein translation, influencing long-term changes in neuronal excitability. No direct behavioral assessment	The current findings do not eliminate alternative hypotheses. Further research is needed to identify proteins involved in excitability changes
Kim and Kaczmarek (2014) [9]	Systematic review	Systematic review	The paper is a review article on Slack channels and their role in intellectual disability related to epilepsy, including malignant migrating partial seizures in infancy, autosomal dominant nocturnal frontal lobe epilepsy, and Ohtahara syndrome, compiling data from various studies	Slack channels are associated with intellectual disability in fragile X syndrome and are linked to severe delays in cognitive development in early-onset epileptic encephalopathies	Limited understanding of how Slack channel activity is altered in different conditions. Hypotheses about mechanisms are not experimentally tested
Bausch et al. (2015) [11]	Experimental study	Kcnt1 null mice and wild type	Use of the Kcnt1 null mouse model to assess Slack channel role in memory and learning. Morris water maze (MWM) task for spatial learning and reversal learning. Open-field test for explorative motivation and locomotor activity. Anxiety behavior by the dark light box test. Circular maze for reference and reversal learning	The study demonstrates that Slack channels are required for cognitive flexibility, spatial learning, and adapting to new situations, are involved in regulating anxiety-like behaviors in mice, but not for working memory or reference memory. Similar results have been seen in FMRP-deficient mice	Cellular mechanisms affected by Slack deficiency in reversal learning and cognitive flexibility are not well understood. Impact of Slack deficiency on bidirectional synaptic plasticity needs further investigation
Quraishi et al. (2020) [12]	Experimental study	Kcnt1 -/- mice, heterozygous Kcnt1 +/R455H mice, and wild-type mice	Creation of mouse models with deletion of the Kcnt1 gene and the R455H mutation using CRISPR/Cas9. EEG electrode implantation for seizure monitoring.  Electroshock and PTZ chemical induction for seizure susceptibility testing. Behavioral tests: open-field activity, rotarod for motor skill learning, and Lashley III maze for spatial learning. Video EEG monitoring for spontaneous seizures	Complete loss of Kcnt1 produced deficits in open-field behavior, motor skill learning, and anxiety-like behavior, but no defect in spatial learning.  Kcnt1 -/- mice were protected from death after maximum electroshock-induced seizures. Heterozygous Kcnt1 +/R455H mice had increased seizure susceptibility and activity, supporting the hypothesis that increased K Na current leads to epilepsy	The study tested adult animals, but the human disease presents in infancy.  The knockout and knock-in mice were on different background strains and were compared to their separate wild types, but not compared directly to each other. The seizure induction tests did not follow the NINDS antiepileptic drug screening program protocol
Kessi et al. (2020) [13]	Systematic review	Systematic review	Conducted a systematic review following PRISMA guidelines. Searched PubMed and Embase databases up to October 2019. Used specific search strategies focusing on intellectual disability and potassium channelopathies. Included cohorts, case-controls, cross-sectionals, case series, and case reports. Selected studies with patients having ID/GDD and potassium channel gene mutations. Excluded studies with other channelopathies or gene mutations	Potassium channelopathies play a significant role in initiating intellectual disability (ID), with both gain-and loss-of-function mutations leading to ID. A total of 19 potassium channelopathies affecting various genes are associated with ID. The mechanisms by which gain-and loss-of-function mutations lead to ID are not fully understood, necessitating further research	Lack of available information on distinct animal models. Paucity of animal studies on the mechanisms of ID related to potassium channelopathies. Limited benefits of available treatment options (channel openers or blockers). Need for further research on the effects of gain-and loss-of-function mutations. Need for additional research on interactions between channels and other proteins. Limited understanding of gene therapies/editing as potential treatments
Gong et al. (2021) [14]	Case report	Case report	Whole-exome sequencing to identify likely pathogenic variants in KCNT2 causing developmental and epileptic encephalopathies (DEEs). Retrospective collection and analysis of clinical data. Confirmation of variants using conventional Sanger sequencing. Pathogenicity analysis using PolyPhen-2 and MutationTaster. Classification of variants as likely pathogenic based on the American College of Medical Genetics (ACMG) guidelines	The study presents detailed clinical features and genetic analysis of two patients with KCNT2-related DEE, expanding the known spectrum of KCNT2 mutations.  IS and EIMFS are identified as the most common phenotypes caused by pathogenic mutations in KCNT2. Both gain- and loss-of-function mutations can lead to EIMFS, and quinidine is suggested as a potential personalized medicine approach for KCNT2-related DEE	Small sample size, difficulty in making genotype-phenotype correlations, need for additional cases to clarify correlations, need for further clinical follow-up to understand long-term effects of quinidine
Wu et al. (2024) [15]	Experimental study	Rat PFC neurons	HCN and Slack channels co-immunoprecipitate and colocalize at postsynaptic spines of PFC pyramidal neurons. Whole-cell voltage clamp recordings for electrophysiological assessment. Behavioral experiments using the delayed alternation test for spatial working memory. Stereotaxic surgery for drug infusion	The regulation of working memory by HCN channels in PFC pyramidal neurons is mediated by an HCN-Slack channel complex that links activation of HCN channels to suppression of neuronal excitability. Blocking either HCN or Slack channels improves working memory performance in rats. The regulation of working memory by HCN channels is mediated by an HCN-Slack channel complex that suppresses neuronal excitability	Further genetic studies are needed to establish the specific function of the HCN-Slack channel complex in working memory regulation
Malone et al. (2025 [16]	Experimental study	Cell lines and primary cortical neurons	Constitutively active Slack mutation and pharmacological stimulation. Immunoprecipitation to study Slack-FMRP/CYFIP1 interaction. Reporter construct (dendra2-actin) for translation measurement. Puromycin incorporation assays for translation regulation. FRAP for real-time dendra2-actin fluorescence monitoring. Experiments in HEK cells and primary cortical neurons using siRNA for FMRP and CYFIP1 knockdown to study translation	Activation of Slack potassium channels triggers the translocation of FMRP and CYFIP1 from eIF4E, stimulating mRNA translation initiation in both cell lines and neurons, affecting the synthesis of β-actin. Dysregulation of translation by Slack mutations may contribute to intellectual disability	Potential off-target effects of quinidine cannot be concluded on K flux and translation. Discrepancy in measuring fluorescence versus protein levels