# KCC2 activation during postnatal development alleviates long-term deficits in CDKL5-deficient mice

## TL;DR

Treating CDKL5-deficient mice with a KCC2 activator during early development reduces seizures and improves cognitive and social behavior in adulthood.

## Contribution

OV350 treatment during a critical developmental window alleviates long-term deficits in CDKL5-deficient mice.

## Key findings

- OV350 treatment reduced infantile spasms in Cdkl5 knockout mice.
- Adult mice treated with OV350 showed reduced seizure susceptibility and improved cognitive and behavioral deficits.
- KCC2 phosphorylation and expression were altered in CDD mice during postnatal development.

## Abstract

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe developmental and epileptic encephalopathy characterized by early onset drug-resistant seizures and later cognitive and social impairments. Existing therapies primarily involve antiseizure medications, which have sedative side effects and lack effective treatments for behavioral impairments. Potassium chloride cotransporter (KCC2) activity is regulated by phosphorylation and is a crucial component of the GABAergic inhibitory system. However, KCC2 dysfunction in CDD remains poorly understood. Here, to investigate potential KCC2 dysfunction, we used a constitutive Cdkl5 knockout mouse model of CDD. We used liquid chromatography coupled with tandem mass spectrometry and quantitative analysis to examine the unbiased phosphorylation of KCC2. We observed aberrant KCC2 phosphorylation and reduced expression, suggesting reduced KCC2 activity. Examining developmental KCC2 changes revealed significant alterations in key phosphorylation residues and decreased expression between postnatal days 14 and 21. Treatment with the KCC2 activator (OV350) between p10 and p21 saw a significant reduction in infantile spasms compared to vehicle-treated Cdkl5 knockout mice. Remarkably, when these mice were adults, the mice that received OV350 as pups had reduced seizure susceptibility and their cognitive and behavioral deficits were alleviated. These findings indicate that enhancing KCC2 function during a critical developmental window may be a promising therapeutic strategy for CDD and other developmental and epileptic encephalopathies.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe brain disorder causing seizures and developmental issues in children. Here researchers explored a new approach using a molecule called OV350 to enhance the activity of a protein called KCC2, which helps regulate brain cell activity. The researchers used mice lacking CDKL5 to mimic human CDD. They treated these mice with OV350 during a critical development period to see if it could improve symptoms. The study involved both male and female mice, and the treatment aimed to boost KCC2 activity, which is crucial for normal brain function. The results showed that OV350 treatment reduced seizure severity and improved social behavior and memory in adult mice. This suggests that enhancing KCC2 activity during early development can help mitigate some CDD symptoms.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.