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

Abstract

Encoding new information in the brain requires changes in synaptic strength. Neuromodulatory transmitters can facilitate synaptic plasticity by modifying the actions and expression of specific signaling cascades, transmitter receptors and their associated signaling complexes, genes, and effector proteins. One critical neuromodulator in the mammalian brain is norepinephrine (NE), which regulates multiple brain functions such as attention, perception, arousal, sleep, learning, and memory. The mammalian hippocampus receives noradrenergic innervation and hippocampal neurons express β-adrenergic receptors, which are known to play important roles in gating the induction of long-lasting forms of synaptic potentiation. These forms of long-term potentiation (LTP) are believed to importantly contribute to long-term storage of spatial and contextual memories in the brain. In this review, we highlight the contributions of noradrenergic signaling in general and β-adrenergic receptors in particular, toward modulating hippocampal LTP. We focus on the roles of NE and β-adrenergic receptors in altering the efficacies of specific signaling molecules such as NMDA and AMPA receptors, protein phosphatases, and translation initiation factors. Also, the roles of β-adrenergic receptors in regulating synaptic "tagging" and "capture" of LTP within synaptic networks of the hippocampus are reviewed. Understanding the molecular and cellular bases of noradrenergic signaling will enrich our grasp of how the brain makes new, enduring memories, and may shed light on credible strategies for improving mental health through treatment of specific disorders linked to perturbed memory processing and dysfunctional noradrenergic synaptic transmission.

Figure 1.

Down-regulation of protein phosphatase 1 following β-AR activation. Protein phosphatase 1 dephosphorylates a number of synaptic proteins with important roles in LTP induction including CaMKII, NMDARs, and stargazin as well as β₂-ARs. The activity of protein phosphatase 1 (PP1) at synapses is regulated by inhibitor-1 (Inh-1), a regulatory protein that is phosphorylated by PKA and dephosphorylated by protein phosphatase 2B (calcineurin). Inhibitor-1 phosphorylation by PKA following β-AR activation leads to an inhibition of protein phosphatase 1 thereby facilitating protein phosphorylation needed for LTP induction.

Figure 2.

Modulation of NMDAR activity mediated by PKA activation downstream from β-AR activation. PKA activation enhances NMDAR activity by phosphorylating sites in the cytoplasmic C-terminal tails of NMDAR GluN1, GluN2A, and GluN2B subunits. In addition, PKA phosphorylates and inhibits Kv4.2 and SK2 type potassium channels present in dendritic spines, thereby enhancing NMDAR activation by facilitating spine depolarization at active synapses.

Figure 3.

β-AR signaling complexes and regulation of AMPARs. The scaffolding protein PSD-95 interacts with the AMPAR-associated protein stargazin (stg), β-ARs, and AKAPs to form a signaling complex. PKA is recruited into the complex via interactions with AKAPs, thus enabling rapid and efficient phosphorylation of AMPARs following β-AR activation. Phosphorylation of AMPARs by PKA enhances ion channel open probability and facilitates the trafficking of AMPAR to the plasma membrane.

Figure 4.

Translational control by ERK and mTOR. Activation of β-ARs during synaptic stimulation promotes translation initiation through ERK and mTOR pathways. mTOR phosphorylates and inhibits 4E-BP2 (4E-binding protein 2), releasing eukaryotic initiation factor 4E (eIF4E) from repression by 4E-BP2. eIF4E assists translation initiation by binding to eIF4G to form the initiation complex eIF4F. mTOR also activates S6 kinase (S6K), which phosphorylates ribosomal protein S6 to increase synthesis of translation regulatory proteins such as eukaryotic elongation factor 2 (eEF2), poly(A) binding protein (PABP), and S6 itself. ERK may cross-talk with the mTOR pathway via ribosomal S6 kinase (RSK), phosphoinositide-dependent kinase-1 (PDK1), and protein kinase-B (Akt). Diagram is simplified.