Activation of KCC2 during development alleviates cognitive, behavioral, and neural excitability in adult CDKL5-deficient mice DOI Open Access
Muhammad Nauman Arshad,

Christopher E. Bope,

Jacob S Dengler

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 26, 2025

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy (DEE) characterized by severe drug-resistant disorders beginning in early childhood, along with cognitive social impairments later childhood 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 or behavioral this disorder. Postnatal development expression of CDKL5 has similar timeline as the activity potassium chloride co-transporter (KCC2), maturation prerequisite switch to fast synaptic hyperpolarizing inhibition mediated g-aminobutyric acid type A receptors (GABA R). This GABA determined changes phosphorylation multiple residues KCC2. During initial postnatal period, dramatic occur major neuronal circuits formed, laying down pathways important memory consolidation processing. Currently, knowledge gap exists understanding KCC2 dysfunction CDD. adult Cdkl5 KO mice we found aberrant expression, such that profile appeared immature. We examined observed significant alterations key decreased from p14 p21. Because loss-of-function been strongly correlated excessive excitation, impairments, seizure susceptibility, spatial memory, interaction following once daily administration activator (OV350), vehicle, infant mice. more susceptible kainate-induced seizures, show poor sociability deficits learning compared WT Twelve days OV350 treatment infants (p10 p21) prevented benzodiazepine-resistant seizures alleviated contrast, 12 had limited ability alleviate deficits. summary, study demonstrates enhancing function may be potential therapeutic target other DEEs. However, intervention during critical windows crucial optimal outcomes.

Язык: Английский

Activation of KCC2 during development alleviates cognitive, behavioral, and neural excitability in adult CDKL5-deficient mice DOI Open Access
Muhammad Nauman Arshad,

Christopher E. Bope,

Jacob S Dengler

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 26, 2025

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy (DEE) characterized by severe drug-resistant disorders beginning in early childhood, along with cognitive social impairments later childhood 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 or behavioral this disorder. Postnatal development expression of CDKL5 has similar timeline as the activity potassium chloride co-transporter (KCC2), maturation prerequisite switch to fast synaptic hyperpolarizing inhibition mediated g-aminobutyric acid type A receptors (GABA R). This GABA determined changes phosphorylation multiple residues KCC2. During initial postnatal period, dramatic occur major neuronal circuits formed, laying down pathways important memory consolidation processing. Currently, knowledge gap exists understanding KCC2 dysfunction CDD. adult Cdkl5 KO mice we found aberrant expression, such that profile appeared immature. We examined observed significant alterations key decreased from p14 p21. Because loss-of-function been strongly correlated excessive excitation, impairments, seizure susceptibility, spatial memory, interaction following once daily administration activator (OV350), vehicle, infant mice. more susceptible kainate-induced seizures, show poor sociability deficits learning compared WT Twelve days OV350 treatment infants (p10 p21) prevented benzodiazepine-resistant seizures alleviated contrast, 12 had limited ability alleviate deficits. summary, study demonstrates enhancing function may be potential therapeutic target other DEEs. However, intervention during critical windows crucial optimal outcomes.

Язык: Английский

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