|คาสิโนไทย||Memory Extinction: The Role of Dopamine||Memory|
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.
D2 Receptor Signaling
D2 receptor (D2R) mediates two major pathways: adenylate cyclase (AC) and β-arrestin (βArr) (คาสิโนไทยBozzi 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.
In schizophrenia, memory extinction is impaired (Holt et al., 2009; คาสิโนไทย). Strikingly, schizophrenia is also characterized by abnormal dopamine signaling. Its underlying mechanism is discussed in Paper 25.
Author: Frank Lee