Memory  >   Memory Extinction: The Role of Dopamine

Dopamine has five known receptor subtypes, designated as D1 - D5. They belong to G protein-coupled receptors. In most reports, activation of either D1 or D2 receptor by dopamine promoted memory extinction (Abraham et al., 2014; Abraham et al., 2016; Mueller et al., 2010). Its underlying mechanism is discussed in this chapter.


Figure 23-1. The effects of D1R and D2R signaling on memory retrieval/extinction.
(1) D2R signaling promotes extinction via adenylate cyclase (AC, also known as adenylyl cyclase) pathway and β-arrestin (βArr) pathway.
(2) D1R signaling facilitates retrieval via the AC pathway, but promotes extinction through the PLC pathway. However, in the presence of DARPP-32, Cdk5 may bias the D1R signaling toward memory extinction by converting DARPP-32 into an inhibitor of PKA.

D2 Receptor Signaling

D2 receptor (D2R) mediates two major pathways: adenylate cyclase (AC) and β-arrestin (βArr) (Bozzi and Borrelli, 2013). Activation of AC stimulates the production of cAMP, which may enhance the activity of protein kinase A (PKA). As described in Chapter 13, PKA facilitates memory retrieval (or prevents memory extinction). Since D2R signaling inhibits AC, the D2R/AC pathway should promote memory extinction.

In the D2R/βArr pathway, D2R stimulates the formation of a complex containing βArr, protein phosphatase 2A (PP2A) and Akt such that PP2A can dephosphorylate and inactivate Akt (Beaulieu et al., 2005). The inactivation of Akt also promotes memory extinction through a mechanism involving glycogen synthase kinase 3 (GSK-3) and activity-regulated cytoskeletal-associated (Arc) protein. In the dendritic spine, the CABT complex may bind either filamenous actin (F-actin) or GluN2B (Chapter 20). Binding of CABT to F-actin would not block NMDAR currents. However, if F-actin is depolymerized, CABT would be forced to bind and block GluN2B-NMDARs, thereby promoting memory extinction. Arc is known to prevent F-actin depolymerization (Bramham et al., 2008). A recent study demonstrates that GSK-3 promotes Arc degradation (Gozdz et al., 2017).

GSK-3 has two isoforms: GSK-3α and GSK-3β. They are constitutively active, but can be inactivated through the phosphorylation of a single residue: serine 21 for GSK-3α and serine 9 for GSK-3β. Akt may phosphorylate GSK-3 and inhibit its activity. Therefore, inactivation of Akt can augment GSK-3 activity to degrade Arc, facilitating the occlusion of GluN2B-NMDARs by CABT, and consequently promoting memory extinction (Figure 23-1).

D1 Receptor Signaling

D1R mediates two well-established pathways: AC and phospholipase C (PLC). In contrast to D2R signaling which inhibits AC, the D1R signaling activates AC. Therefore, the D1R/AC pathway should facilitates memory retrieval by enhancing PKA activity. The D1R/PLC pathway, however, could promote memory extinction. Activation of PLC is known to increase Ca2+ level (see this article), which in turn can activate calcineurin. Once activated, calcineurin may stimulate cofilin to depolymerize F-actin (Wang et al., 2005), causing CABT to switch binding partner from F-actin to GluN2B-containing NMDARs, thereby resulting in NMDAR extinction (Chapter 20). In addition, calcineurin may activate the transcription factor, nuclear factor of activated T-cells (NFAT), which targets the key player in long-term memory extinction: BDNF (Chapter 19 and Chapter 22).

The above discussion shows that the D1R signaling could lead to two opposite results: facilitating memory retrieval by enhancing PKA activity and promoting memory extinction by activating calcineurin. Which one will dominate may depend on Dopamine and cAMP-regulated phosphoprotein Mr 32,000 (DARPP-32). Phosphorylation at Thr-75 by Cdk5 converts DARPP-32 into an inhibitor of PKA (Belkhiri et al., 2016). Hence, in the presence of DARPP-32, Cdk5 may bias the D1R signaling toward memory extinction.


Figure 23-2. Regulation of PKA and PP1 (protein phosphatase 1) by multisite phosphorylation of DARPP-32. Note that phosphorylation at T75 by Cdk5 converts DARPP-32 into an inhibitor of PKA. [Source: Belkhiri et al., 2016]

In schizophrenia, memory extinction is impaired (Holt et al., 2009; Holt et al., 2012). Strikingly, schizophrenia is also characterized by abnormal dopamine signaling. Its underlying mechanism is discussed in Paper 25.


Author: Frank Lee
First published: November, 2018