Grin2a Dysfunction Impairs Cognitive Flexibility by Disrupting LC Modulation of mPFC Circuits

Cognitive flexibility, a key executive function, is impaired in psychiatric disorders involving prefrontal cortical dysfunction. The medial prefrontal cortex (mPFC) regulates cognitive flexibility and receives noradrenergic input from the locus coeruleus (LC). Mutations in GRIN2A, encoding GluN2A-containing NMDA receptors, impair cognitive flexibility and psychiatric resilience, yet the circuit mechanisms remain unclear. Optogenetic LC[->]mPFC activation improved reversal learning in wild-type and Grin2a heterozygous (HET) mice but not in knockouts (KO), indicating a loss of noradrenergic modulation. Grin2a mutants displayed disrupted gamma and high-frequency oscillations (HFOs) in the mPFC. Exogenous norepinephrine failed to restore oscillatory activity, implicating 2-adrenoceptors in NE-driven cortical dynamics. Increased LC innervation and norepinephrine transporter (NET) expression in Grin2a mutants suggest excessive noradrenergic input and impaired NE clearance. These findings identify GluN2A as essential for LC-driven prefrontal network synchronization and cognitive flexibility, offering insights into NE dysfunction in psychiatric disorders.