Memory  >   Memory Retrieval: The Role of Norepinephrine

Memory retrieval is a process that reactivates extinguished engram cells. This requires the generation of NMDA plateaus in the memory units that encode the memory. Two events are necessary for the generation of NMDA plateaus: (1) recovery of NMDAR extinction (i.e., dissociation of the CABT complex from NMDARs), and (2) a substantial glutamate pond. The source of glutamate may come from glial cells or glutamatergic neurons stimulated by memory recall cues. The recovery of NMDAR extinction requires elevated PKA activity to phosphorylate the GluN2B subunit, thereby leading to dissociation of the CABT complex from NMDARs (Chapter 13).

Norepinephrine (NE), also called noradrenaline, is a neurotransmitter produced mainly in the locus coeruleus (a small brain region within the brainstem). In adult humans, the locus coeruleus contains less than 50,000 noradrenergic neurons that release primarily NE. However, they project to widespread brain areas, including hippocampus, cerebral cortex, basolateral amygdala and striatum (Hansen, 2017; Ferrucci et al., 2013), where NE may bind to specific receptors, triggering a series of signaling cascades. The NE receptors are collectively referred to as "adrenergic receptors" (ARs).

NE has been shown to promote memory retrieval via the stimulation of β1ARs, the production of cAMP, and the activation of PKA (Zhang et al., 2013). Other studies have also established that NE may facilitate memory retrieval by acting on β1ARs (Devauges and Sara, 1991; Murchison et al., 2004; Murchison et al., 2011; Fitzgerald et al., 2016). Conversely, NE may impair memory retrieval via another subtype: β2ARs (Schutsky et al., 2011a; Schutsky et al., 2011b), which leads to the reduction of PKA activity (Figure 24-1).


Figure 24-1. Norepinephrine induced signaling.
(A) Binding to β1AR induces dissociation of Gαs from Gβγ. Gαs may activate adenylyl cyclase (AC) to increase cAMP levels and PKA activity, thereby facilitating memory retrieval.
(B) Binding to β2AR induces dissociation of Gαi from Gβγ. Gαi may inactivate AC to reduce cAMP levels and PKA activity, consequently impairing memory retrieval.
[Adapted from: Wikipedia]

The adrenergic receptors belong to G protein-coupled receptors. A G protein consists of three subunits: α, β and γ. Before activation, they are assembled together. Gβ and Gγ are tightly bound, whereas Gα may dissociate from Gβγ, depending on whether it is bound with GDP (guanosine diphosphate) or GTP (guanosine triphosphate). In the resting state, Gα is bound with GDP, facilitating the assembly of three subunits. After activation, the GDP bound to Gα will be replaced by GTP, promoting dissociation of Gα from Gβγ. The separated Gα and Gβγ can then act on specific targets, known as effectors. The GTP on Gα cannot last long, because Gα has the enzymatic activity to hydrolyze it into GDP, thereby returning to the resting state.

Gα has several isoforms, such as Gαs, Gαi and Gαq. Gαs may stimulate the production of cAMP by activating adenylyl cyclase (AC) which is an enzyme capable of converting ATP into cAMP. Gαi has the inhibitory effect on cAMP production by inactivating AC. Since the PKA activity depends on cAMP, the receptors coupled to Gαs will increase, while coupling to Gαi will decrease, the PKA activity. It has been well documented that β1ARs are coupled to Gαs (Schutsky et al., 2011a). This explains why NE promotes retrieval via the stimulation of β1ARs.


Author: Frank Lee
First published: November, 2017
Last updated: July, 2018