Neuromodulatory signaling in hippocampus-dependent memory retrieval

Abstract

Considerable advances have been made toward understanding the molecular signaling events that underlie memory acquisition and consolidation. In contrast, less is known about memory retrieval, despite its necessity for utilizing learned information. This review focuses on neuromodulatory and intracellular signaling events that underlie memory retrieval mediated by the hippocampus, for which the most information is currently available. Among neuromodulators, adrenergic signaling is required for the retrieval of various types of hippocampus-dependent memory. Although they contribute to acquisition and/or consolidation, cholinergic and dopaminergic signaling are generally not required for retrieval. Interestingly, while not required for retrieval, serotonergic and opioid signaling may actually constrain memory retrieval. Roles for histamine and non-opioid neuropeptides are currently unclear but possible. A critical effector of adrenergic signaling in retrieval is reduction of the slow afterhyperpolarization mediated by β1 receptors, cyclic AMP, protein kinase A, Epac, and possibly ERK. In contrast, stress and glucocorticoids impair retrieval by decreasing cyclic AMP, mediated in part by the activation of β2 -adrenergic receptors. Clinically, alterations in neuromodulatory signaling and in memory retrieval occur in Alzheimer's disease, Down syndrome, depression, and post-traumatic stress disorder, and recent evidence has begun to link changes in neuromodulatory signaling with effects on memory retrieval.

Keywords: CA1; adrenergic; cyclic AMP; glucocorticoid; slow afterhyperpolarization.

FIGURE 1.

NE, β-adrenergic signaling, and protein kinase A are required for intermediate-term contextual memory retrieval. A: NE/E-deficient Dbh^−/− mice exhibit impaired contextual fear memory retrieval beginning 1–2 h after training and lasting for ~4 days. Controls are Dbh^+/− mice that have normal tissue NE/E content. B: Wild-type rats administered 1 mg/kg of the β-adrenergic receptor antagonist (−)-propranolol (Prop) 30 min before testing exhibit a similar impairment in intermediate-term context retrieval relative to rats treated with saline (Sal). C: Wild-type mice infused with 2 mg per dorsal hippocampus of the myristoylated, membrane permeable protein kinase A inhibitory peptide PKI (Sal infusion for reference) 15 min before testing exhibit reduced context retrieval for the first 3 days after training. Similarly, wild-type mice infused with 2 μg per dorsal hippocampus of the L-type voltage-dependent Ca²⁺ channel enhancer BayK8644 (Bay) with vehicle (Veh) infusion for reference 15 min before testing exhibit reduced context retrieval for the first 3 days after training. For all figures, each data point represents a group of animals tested only once (n ≥ 5), and symbols of significance for post-hoc comparisons are * P < 0.05, ^ P < 0.01, # P < 0.001. Data are from Murchison et al., 2004; Ouyang et al., 2008; and Zhang et al., 2013 with some updating and modification of format.

FIGURE 2.

NE, β₁ receptors, and cAMP facilitate retrieval via reduction of the slow afterhyperpolarization (sAHP). Excitation of CA1 pyramidal neurons opens L-type voltage-dependent Ca²⁺ channels. In the absence of NE, the resulting Ca²⁺ influx activates K⁺ channels that underlie the sAHP causing accommodation of firing. During arousal, NE is released and stimulation of adenylyl cyclase (AC) by β₁ receptors results in cAMP-dependent signaling by protein kinase A (PKA) and the exchange protein activated by cAMP (Epac). PKA may phosphorylate proteins (K⁺ channel subunits and/or associated regulators that underlie the sAHP) to decrease their activity (as indicated by a dashed line). This reduces the sAHP and accommodation, allowing excitatory input to CA1 to be more faithfully transmitted as excitatory output. In this way NE would act to facilitate hippocampal output and thus memory retrieval during arousal. Although both are required for the facilitation of retrieval by NE, the relationship between PKA and Epac signaling is currently unclear. It is possible that Epac signaling leads to the activation of ERK, and that ERK acts in a manner similar to PKA to reduce the sAHP. That this retrieval-relevant signaling occurs in CA1 pyramidal neurons is hypothesized but not yet tested.

FIGURE 3.

A convergence of glucocorticoid and adrenergic signaling mediate the effects of stress on retrieval. During arousal, moderate levels of NE stimulate β₁ receptors, G_s, adenylyl cyclase (AC), and cAMP signaling to facilitate retrieval. During stress, corticosterone (Cort) interacts with higher levels of NE to stimulate β₂ receptors (which are less sensitive to NE relative to β₁ receptors) and G_i to impair cAMP signaling and retrieval. A requirement for the glucocorticoid receptor (GR) in mediating the effects of Cort is hypothesized but not yet fully tested.