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 b-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 b-adrenergic receptors in particular, toward modulating hippocampal LTP. We focus on the roles of NE and b-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 b-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.Synaptic plasticity is a fundamental property of nervous system function. A neuron's ability to alter the strength of its synaptic connections is thought to be the foundation for multiple processes, including learning and memory. Synaptic plasticity is not a single, unitary cellular process, but rather an extremely diverse phenomenon that encompasses many forms and functions. Synapses are dynamic by nature, and only through elucidation of the mechanisms that govern their organization and reorganization can we hope to fully understand how the brain processes and stores information.Acting as potent regulatory agents, neuromodulatory transmitters can significantly alter the properties of neurons at cellular and network levels. Specifically, the modulatory role of the noradrenergic system has been extensively characterized, in part because of the system's anatomically ubiquitous connections. Noradrenergic fibers originate mainly in the locus coeruleus (LC) and project widely throughout the forebrain, with dense innervation of the hippocampus, amygdala, and thalamus (Sara 2009). These connections, especially within the hippocampus, strongly modulate synaptic strength and neural network physiology, which lead to significant alterations in learning, memory, attention, and perception. Noradrenergic receptor signal...

Previous studies have provided strong support for the notion that NMDAR-mediated increases in postsynaptic Ca2ϩ have a crucial role in the induction of long-term depression (LTD). This view has recently been challenged, however, by findings suggesting that LTD induction is instead attributable to an ion channel-independent, metabotropic form of NMDAR signaling. Thus, to explore the role of ionotropic versus metabotropic NMDAR signaling in LTD, we examined the effects of varying extracellular Ca 2ϩ levels or blocking NMDAR channel ion fluxes with MK-801 on LTD and NMDAR signaling in the mouse hippocampal CA1 region. We find that the induction of LTD in the adult hippocampus is highly sensitive to extracellular Ca 2ϩ levels and that MK-801 blocks NMDAR-dependent LTD in the hippocampus of both adult and immature mice. Moreover, MK-801 inhibits NMDAR-mediated activation of p38-MAPK and dephosphorylation of AMPAR GluA1 subunits at sites implicated in LTD. Thus, our results indicate that the induction of LTD in the hippocampal CA1 region is dependent on ionotropic, rather than metabotropic, NMDAR signaling.

Behavioral, physiological, and anatomical evidence indicates that the dorsal and ventral zones of the hippocampus have distinct roles in cognition. How the unique functions of these zones might depend on differences in synaptic and neuronal function arising from the strikingly different gene expression profiles exhibited by dorsal and ventral CA1 pyramidal cells is unclear. To begin to address this question, we investigated the mechanisms underlying differences in synaptic transmission and plasticity at dorsal and ventral Schaffer collateral (SC) synapses in the mouse hippocampus. We find that, although basal synaptic transmission is similar, SC synapses in the dorsal and ventral hippocampus exhibit markedly different responses to frequency patterns of stimulation. In contrast to dorsal hippocampus, frequency stimulation fails to elicit postsynaptic complex-spike bursting and does not induce LTP at ventral SC synapses. Moreover, EPSP-spike coupling, a process that strongly influences information transfer at synapses, is weaker in ventral pyramidal cells. Our results indicate that all these differences in postsynaptic function are due to an enhanced activation of SK-type K ϩ channels that suppresses NMDAR-dependent EPSP amplification at ventral SC synapses. Consistent with this, mRNA levels for the SK3 subunit of SK channels are significantly higher in ventral CA1 pyramidal cells. Together, our findings indicate that a dorsal-ventral difference in SK channel regulation of NMDAR activation has a profound effect on the transmission, processing, and storage of information at SC synapses and thus likely contributes to the distinct roles of the dorsal and ventral hippocampus in different behaviors.

Background: AMPA receptor (AMPAR) GluA1 subunits contain multiple phosphorylation sites. Results: Distinct Ca 2ϩ -dependent signaling pathways regulate GluA1 phosphorylation at Thr-840 and Ser-845, and phosphorylation of one site inhibits phosphorylation of the other. Conclusion:Interactions between Thr-840 and Ser-845 provides a mechanism for conditional regulation of AMPARs. Significance: Our results reveal a novel mechanism for regulating AMPAR function at excitatory synapses.

Dephosphorylation of AMPA receptor (AMPAR) GluA1 subunits at two sites, serine 845 (S845) and threonine 840 (T840), is thought to be involved in NMDA receptor-dependent forms of long-term depression (LTD). Importantly, the notion that dephosphorylation of these sites contributes to LTD assumes that a significant fraction of GluA1 subunits are basally phosphorylated at these sites. To examine this question, we used immunoprecipitation/depletion assays to estimate the proportion of GluA1 subunits basally phosphorylated at S845 and T840. Although dephosphorylation of S845 is thought to have a key role in LTD, our results indicate that few GluA1 subunits in hippocampal neurons are phosphorylated at this site. In contrast, 50% of GluA1 subunits are basally phosphorylated at T840, suggesting that dephosphorylation of this site can contribute to the down-regulation of AMPAR-mediated synaptic transmission in LTD.

Activation of β-adrenergic receptors (β-ARs) not only enhances learning and memory but also facilitates the induction of long-term potentiation (LTP), a form of synaptic plasticity involved in memory formation. To identify the mechanisms underlying β-AR-dependent forms of LTP we examined the effects of the β-AR agonist isoproterenol on LTP induction at excitatory synapses onto CA1 pyramidal cells in the ventral hippocampus. LTP induction at these synapses is inhibited by activation of SK-type K+ channels, suggesting that β-AR activation might facilitate LTP induction by inhibiting SK channels. However, although the SK channel blocker apamin enhanced LTP induction, it did not fully mimic the effects of isoproterenol. We therefore searched for potential alternative mechanisms using liquid chromatography-tandem mass spectrometry to determine how β-AR activation regulates phosphorylation of postsynaptic density (PSD) proteins. Strikingly, β-AR activation regulated hundreds of phosphorylation sites in PSD proteins that have diverse roles in dendritic spine structure and function. Moreover, within the core scaffold machinery of the PSD, β-AR activation increased phosphorylation at several sites previously shown to be phosphorylated after LTP induction. Together, our results suggest that β-AR activation recruits a diverse set of signaling pathways that likely act in a concerted fashion to regulate LTP induction.