Activation of KCC2 during development alleviates cognitive, behavioral, and neural excitability in adult CDKL5-deficient mice

Abstract

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy (DEE) characterized by severe drug-resistant epileptic disorders beginning in early childhood, along with cognitive and social impairments in later childhood and adulthood. Existing pharmacological therapies for CDD primarily focus on anti-seizure medications, which often have associated sedative side effects. In addition, there are currently no effective treatments for cognitive or behavioral impairments associated with this disorder. Postnatal development expression of CDKL5 has a similar timeline as the developmental activity of the potassium chloride co-transporter (KCC2), the maturation of which is a prerequisite for the developmental switch to fast synaptic hyperpolarizing inhibition mediated by g-aminobutyric acid type A receptors (GABAAR). This developmental GABA switch is determined by changes in the phosphorylation of multiple residues in KCC2. During this initial postnatal period, dramatic changes occur as major neuronal circuits are formed, laying down the initial pathways important for memory consolidation and behavioral processing. Currently, a knowledge gap exists in understanding KCC2 dysfunction in CDD. In adult Cdkl5 KO mice we found aberrant KCC2 phosphorylation and expression, such that KCC2 phosphorylation profile appeared immature. We examined the developmental changes in KCC2 and observed significant alterations in the phosphorylation of key residues and decreased KCC2 expression from p14 to p21. Because KCC2 loss-of-function has been strongly correlated with excessive neuronal excitation, cognitive and behavioral impairments, we examined seizure susceptibility, spatial memory, and social interaction in adult Cdkl5 KO mice following once daily administration of the KCC2 activator (OV350), or vehicle, to infant Cdkl5 KO mice. We found that adult Cdkl5 KO mice are more susceptible to kainate-induced seizures, show poor sociability and deficits in spatial learning and memory compared to WT mice. Twelve days of OV350 treatment as infants (p10 to p21) prevented the development of benzodiazepine-resistant seizures and alleviated cognitive and behavioral deficits in adult Cdkl5 KO mice. In contrast, 12 days of OV350 treatment in adult Cdkl5 KO mice had limited ability to alleviate cognitive and behavioral deficits. In summary, this study demonstrates that enhancing KCC2 function may be a potential therapeutic target for CDD and other DEEs. However, early intervention during critical developmental windows is crucial for optimal outcomes.