<p>Cognitive deficits in executive functions such as working memory and cognitive flexibility are central to many brain disorders, yet effective treatments remain limited. Dysfunction of GluN2A-containing NMDA receptors (NMDAR) contributes to these impairments, and positive allosteric modulators (PAM) that selectively enhance GluN2A function offer a promising strategy to rescue cognitive deficits while preserving physiological neurotransmission. However, it remains unclear whether PAM-driven GluN2A potentiation can rescue mechanistically distinct, pharmacologically induced impairments and whether the efficacy of GluN2A-PAMs differs across executive domains and sexes. Here, we assessed the effects of GNE-5729, a brain-penetrant GluN2A-selective PAM, on executive functions in mice. GNE-5729 showed no overall effect on working memory performance in the Y-maze, but improved performance in mice with low baseline spontaneous alternations, indicating a baseline-dependent effect. It also rescued working memory deficits induced by dl-amphetamine and scopolamine, which disrupt neuromodulatory regulation while leaving NMDAR channels functionally accessible. In contrast, GNE-5729 failed to reverse MK-801-induced impairments, consistent with MK-801’s non-competitive pore blockade of NMDAR. Notably, GNE‑5729 effects showed sex‑dependent patterns, with female mice displaying more pronounced effects. GNE-5729 had no effects on cognitive flexibility in the attentional set-shifting task (ASST) and did not alter prefrontal GluN2A expression, though it disrupted the association between endogenous GluN2A levels and ASST performance observed in controls. Together, these findings indicate that GNE-5729 exerts effects under conditions of reduced baseline performance or disrupted neuromodulatory signaling and demonstrates differential effects across executive domains, supporting a state-dependent therapeutic profile of GluN2A-targeted modulation.</p>