|Memory Retrieval: The Role of Norepinephrine||Memory|
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 a wide variety of brain areas, including hippocampus, cerebral cortex, amygdala and thalamus, where they may bind to specific receptors, triggering a series of signaling cascades. The NE receptors are collectively referred to as "adrenergic receptors".
The idea that NE might play a role in memory retrieval dates back to 1985 (Sara, 1985). Since then, a number of studies have established that NE may facilitate memory retrieval by acting on a subtype of adrenergic receptors: β1 (Devauges and Sara, 1991; Murchison et al., 2004; Murchison et al., 2011; Zhang et al., 2013; Fitzgerald et al., 2016). Conversely, NE may impair memory retrieval via another subtype: β2-adrenergic receptors (β2ARs) (Schutsky et al., 2011a; Schutsky, 2011b). These results are consistent with the general mechanism proposed in Chapter 16, that is, activation of protein kinase A (PKA) facilitates memory retrieval.
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, the production of cAMP, and the activation of PKA (Zhang et al., 2013). On the other hand, β2ARs are coupled to Gαi in the hippocampus. Thus, β2 signaling should decrease cAMP levels and PKA activity (Schutsky et al., 2011a) which, according to the general mechanism proposed in Chapter 16, would impair memory retrieval.
Author: Frank Lee