The widespread noradrenergic innervation in the brain promotes arousal and learning by molecular mechanisms that remain largely undefined. Recent work shows that the β₂-adrenergic receptor (β₂AR) is linked to the AMPA-type glutamate receptor subunit GluA1 via stargazin and PSD-95 (Joiner ML, Lise MF, Yuen EY, Kam AY, Zhang M, Hall DD, Malik ZA, Qian H, Chen Y, Ulrich JD, Burette AC, Weinberg RJ, Law PY, El-Husseini A, Yan Z, Hell JW. EMBO J 29: 482–495, 2010). We now demonstrate that the β₂AR plays a prominent role in long-term potentiation (LTP) induced by a train of 900 stimuli at 5 Hz (prolonged theta-tetanus-LTP, or PTT-LTP) in the hippocampal CA1 region in mice, which requires simultaneous β-adrenergic stimulation. Although PTT-LTP was impaired in hippocampal slices from β₁AR and β₂AR knockout (KO) mice, only β₂AR-selective stimulation with salbutamol supported this PTT-LTP in wild-type (WT) slices, whereas β₁AR-selective stimulation with dobutamine (+ prazosin) did not. Furthermore, only the β₂AR-selective antagonist ICI-118551 and not the β₁AR-selective antagonist CGP-20712 inhibited PTT-LTP and phosphorylation of GluA1 on its PKA site S845 in WT slices. Our analysis of S845A knockin (KI) mice indicates that this phosphorylation is relevant for PTT-LTP. These results identify the β₂AR-S845 signaling pathway as a prominent regulator of synaptic plasticity.