Intranasal administration of KCNN2 blocking peptide improves deficits in cognitive flexibility in mouse model of Fetal Alcohol Spectrum Disorders

Authors

Shahid Mohammad, Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington DC, USA.
Li Wang, Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington DC, USA.
Masaaki Torii, Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington DC, USA.
Kazue Hashimoto-Torii, Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington DC, USA.

Document Type

Journal Article

Publication Date

8-8-2025

Journal

The international journal of neuropsychopharmacology

DOI

10.1093/ijnp/pyaf055

Keywords

Fetal Alcohol Spectrum Disorders; Intranasal administration; KCNN2; cognitive flexibility; prefrontal cortex

Abstract

BACKGROUND: Fetal Alcohol Spectrum Disorders (FASD) show a myriad of cognitive and neurological deficits, with the prevalence estimated to be 1-5 % in children. To date, there are no effective treatments for these deficits in FASD. In a mouse model of FASD, daily intraperitoneal administration of a KCNN2 blocking peptide has been shown to improve motor learning deficits due to upregulation of KCNN2 channels. This study investigates whether intranasal administration of a KCNN2 blocking peptide, Lei-Dab7, can improve cognitive flexibility, specifically reversal learning deficits, in these mice. METHODS: We utilized a mouse model of prenatal alcohol exposure. Cognitive flexibility was assessed using the water T-maze test at postnatal day 40 (P40). Lei-Dab7's specificity and cytotoxicity were evaluated in vitro, and intranasal delivery efficiency was confirmed through immunohistochemistry, quantifying its distribution and binding to neurons with elevated KCNN2 expression in the prefrontal cortex (PFC). RESULTS: Lei-Dab7 showed high specificity and negligible cytotoxicity in vitro. Intranasal administration efficiently delivered Lei-Dab7 to the PFC, where it specifically bound to neurons expressing increased KCNN2 channels. Behavioral tests demonstrated that Lei-Dab7 significantly improved cognitive flexibility, reversing the deficits in the water T-maze test seen in ethanol-exposed mice, without apparent acute physiological adverse effects. CONCLUSIONS: Intranasal administration of KCNN2 blockers, such as Lei-Dab7, represents a promising, non-invasive therapeutic approach for treating cognitive inflexibility and possibly other cognitive dysfunctions associated with FASD.

APA Citation

Mohammad, Shahid; Wang, Li; Torii, Masaaki; and Hashimoto-Torii, Kazue, "Intranasal administration of KCNN2 blocking peptide improves deficits in cognitive flexibility in mouse model of Fetal Alcohol Spectrum Disorders" (2025). GW Authored Works. Paper 7794.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/7794

Department

Pediatrics