GluN2A Enables Noradrenergic Control of Prefrontal Oscillations and Cognitive Flexibility.

Cognitive flexibility-the ability to adapt behavior when contingencies change-is impaired in psychiatric disorders involving prefrontal dysfunction. The medial prefrontal cortex (mPFC) relies on noradrenergic input from the locus ceruleus (LC), yet the molecular mechanisms enabling this neuromodulatory control remain unclear. Here we show that GluN2A-containing NMDA receptors are required for LC-mPFC regulation of network dynamics and reversal learning in male mice. Optogenetic activation of LC→mPFC projections enhanced reversal learning in wild-type (WT) and heterozygous mice but not in global Grin2a knock-outs, whereas LC inhibition impaired performance only in WT animals. In slices, norepinephrine (NE) and LC stimulation induced gamma and high-frequency oscillations in WT mPFC that were blocked by α2-adrenergic antagonism, but these oscillatory responses were undetectable in Grin2a mutants. Grin2a mutants also exhibited increased LC axonal density and elevated NE transporter expression in the prelimbic cortex, consistent with enhanced noradrenergic clearance capacity. Together, these findings identify GluN2A as a key determinant of LC-prefrontal circuit function supporting cognitive flexibility. They suggest that functional deficits in these mutants should be interpreted within the context of compensatory structural hyperinnervation resulting from global GluN2A deficiency, which may reflect a developmental adaptation rather than acute signaling loss. Furthermore, these results promote α2-adrenergic pathways as potential entry points for restoring prefrontal network coordination.