Developmental Regulation of KCC2 Phosphorylation Has Long-Term Impacts on Cognitive Function

Area of Science:

• Neuroscience
• Developmental Biology
• Molecular Biology

Background:

• GABA_A receptor currents transition from excitatory to inhibitory during rodent postnatal development.
• KCC2 protein expression increase is traditionally viewed as the sole driver of this developmental shift.

Purpose of the Study:

• To investigate the role of KCC2 phosphorylation in the developmental shift of GABA_A receptor-mediated currents.
• To determine the impact of altered KCC2 phosphorylation timing on cognitive functions in adulthood.

Main Methods:

• Utilized KCC2-S940A and KCC2-T906A/T1007A knock-in mouse models to study KCC2 phosphorylation.
• Assessed the effects of preventing or altering KCC2 phosphorylation in vivo on developmental timing and cognitive function.

Main Results:

• Preventing KCC2 phosphorylation at S940 delayed, while phosphorylation at T906/T1007 accelerated, the onset of KCC2 function.
• Altered KCC2 function led to long-term deficits in social behavior and memory retention.

Conclusions:

• KCC2 phosphorylation is a critical regulator of the developmental onset of hyperpolarizing GABAergic inhibition.
• Precise regulation of KCC2 phosphorylation is essential for typical neurodevelopment and the establishment of adult cognitive functions.