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 coeruleus (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 and heterozygous mice but not in global Grin2a knockouts, whereas LC inhibition impaired performance only in wild-type animals. In slices, norepinephrine and LC stimulation induced gamma and high-frequency oscillations in wild-type 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 norepinephrine transporter expression in 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.Significance statement Cognitive flexibility is often impaired in psychiatric disorders, yet how norepinephrine engages prefrontal network dynamics remains unclear. We investigate how global GluN2A deficiency affects LC-mPFC dynamics while accounting for potential systemic and developmental contributions. These findings show that global GluN2A deficiency disrupts noradrenergic induction of synchronized oscillatory activity and highlight α2-adrenergic pathways as a candidate therapeutic entry point for improving prefrontal network function. Importantly, our results suggest that functional deficits in global knockout models must be interpreted within the context of compensatory structural changes in circuit architecture, such as hyperinnervation.