β₂-Adrenergic receptor supports prolonged theta tetanus-induced LTP

Abstract

The widespread noradrenergic innervation in the brain promotes arousal and learning by molecular mechanisms that remain largely undefined. Recent work shows that the β(2)-adrenergic receptor (β(2)AR) 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 β(2)AR 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 β(1)AR and β(2)AR knockout (KO) mice, only β(2)AR-selective stimulation with salbutamol supported this PTT-LTP in wild-type (WT) slices, whereas β(1)AR-selective stimulation with dobutamine (+ prazosin) did not. Furthermore, only the β(2)AR-selective antagonist ICI-118551 and not the β(1)AR-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 β(2)AR-S845 signaling pathway as a prominent regulator of synaptic plasticity.

Conversion of short-term potentiation to long-term potentiation in mouse CA1 by coactivation of β-adrenergic and muscarinic receptors

“…We have shown that the effects of ISO are mediated through b1-but not b2-adrenergic receptors, as the facilitative effects of ISO + CCh were blocked by CGP (b1 antagonist) but were preserved in the presence of ICI (b2 antagonist). Recent data suggest that prolonged u-frequency stimulation paired with ISO application induces LTP requiring b2-ARs but not b1 (Qian et al 2012). However, prior evidence generated using b1-AR KO mice found deficits in Q + ISO LTP that was not observed in b2 KOs (Winder et al 1999).…”

“…The relatively low concentrations of ISO or the presence of a second neuromodulatory agonist may also explain the favored initiation of signal mechanisms downstream of b1-ARs, whereas the Qian et al (2012) data were based on the presence of ISO alone which may necessitate the engagement of both receptor subtypes. Future research combining receptor subtype-specific agonists will be required to further delineate the putative interactions of these neuromodulatory signaling mechanisms.…”

β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus

“…For example, b-AR activation enables the induction of protein synthesis-dependent L-LTP by a single 100-Hz train of HFS (Gelinas and Nguyen 2005;Ma et al 2011). Moreover, u-pulse stimulation (TPS; 150-900 stimulation pulses delivered at 5 -10 Hz), a pattern of synaptic stimulation that alone has little or no lasting effect on synaptic strength, can induce LTP if delivered in the presence of b-AR agonists (Thomas et al 1996;Katsuki et al 1997;Moody et al 1998;Winder et al 1999;Brown et al 2000;Gelinas and Nguyen 2005;Havekes et al 2012;Qian et al 2012). The induction of LTP by spike-timing-dependent plasticity protocols, where excitatory postsynaptic potentials elicited by presynaptic fiber stimulation are paired with postsynaptic action potentials evoked by current injection through an intracellular recording electrode, is also enhanced by b-AR activation (Lin et al 2003;Seol et al 2007;Makino et al 2011).…”

Activation of β2-adrenoceptor enhances synaptic potentiation and behavioral memory via cAMP-PKA signaling in the medial prefrontal cortex of rats

“…For example, Qian et al (2012) reported that b2-AR activation supports prolonged hippocampal u-tetanus-LTP (Qian et al 2012), which is an important form of synaptic plasticity for hippocampal functions. McGaugh and co-workers (1991) reported that the infusion of the b2-AR agonist clenbuterol into the amygdala immediately after training enhances memory retention in an inhibitory avoidance task (Introini-Collison et al 1991).…”