Intranasal Administration of KCNN2 Blocking Peptide Improves Deficits in Cognitive Flexibility in Mouse Model of
Shahid Mohammad1, Li Wang1, Masaaki Torii1,2
1Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington, DC, United States.
Insights
Intranasal KCNN2 blocking peptide Lei-Dab7 effectively improved cognitive flexibility in a mouse model of Fetal Alcohol Spectrum Disorders (FASD). This non-invasive treatment offers a promising therapeutic avenue for FASD-related cognitive deficits.
Area of Science:
- Neuroscience
- Pharmacology
- Developmental Biology
Background:
- Fetal Alcohol Spectrum Disorders (FASD) are prevalent neurodevelopmental conditions causing significant cognitive and neurological deficits.
- Current treatments for FASD-related cognitive impairments are lacking.
- Previous studies indicated KCNN2 channel upregulation contributes to motor deficits in FASD models.
Purpose of the Study:
- To investigate the efficacy of intranasal administration of a KCNN2 blocking peptide, Lei-Dab7, in improving cognitive flexibility in a mouse model of FASD.
- To assess Lei-Dab7's safety and delivery efficiency.
Main Methods:
- Utilized a mouse model of prenatal alcohol exposure.
- Assessed cognitive flexibility using the water T-maze test.
- Evaluated Lei-Dab7's specificity, cytotoxicity, and intranasal delivery efficiency to the prefrontal cortex (PFC).
Main Results:
- Lei-Dab7 demonstrated high specificity and low cytotoxicity in vitro.
- Intranasal Lei-Dab7 efficiently reached the PFC and targeted neurons with elevated KCNN2 expression.
- Treated mice showed significant improvement in cognitive flexibility in the water T-maze test.
Conclusions:
- Intranasal Lei-Dab7 administration effectively reversed cognitive inflexibility in an FASD mouse model.
- This non-invasive approach shows promise for treating cognitive deficits in FASD.
- Further research may explore Lei-Dab7 for other FASD-related cognitive dysfunctions.
Background:
Fetal alcohol spectrum disorders (FASD) show a myriad of cognitive and neurological deficits, with the prevalence estimated to be 1% to 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 potassium calcium-activated channel subfamily N member 2 (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, Leiurotoxin-1 Dab7 (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. 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.
Results:
Lei-Dab7 showed high specificity and negligible cytotoxicity in vitro. Intranasal administration efficiently delivered Lei-Dab7 to the prefrontal cortex, 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.
