|คาสิโนไทย||The Extinction (Desensitized) State of NMDA Receptors||Memory|
In the dentate gyrus of the hippocampus, more than 90% of granule cells are silent, namely, they do not respond to environmental stimuli, and no longer engage in acquiring new memory (Alme et al., 2010). Silent cells are also quite prevalent in the neocortex (คาสิโนไทยBarth and Poulet, 2012), and other subregions of the hippocampus (Thompson and Best, 1989). What causes these cells to become silent?
For memory engram cells, neuronal firing depends largely on the NMDA plateau produced by a cluster of synapses. The action potential can be generated only when the NMDA plateau is produced. In silent cells, the NMDA receptors (NMDARs) may somehow be inhibited such that they are unable to produce NMDA plateau. Evidence will be presented in this and subsequent chapters for the CABT Hypothesis that NMDARs could be blocked by the CABT complex, which consists of a CRMP2 monomer, alpha (α) and beta (β) tubulin. (Figure 12-1).
Collapsin response mediator protein-2 (CRMP2) was first discovered as a principal regulator of axonal extension (Goshima et al., 1995). Since then, its functions have expanded to include dendritic branching (Niisato et al., 2013), axonal transport, protein endocytosis, calcium channel regulation and neurotransmitter release (Khanna et al., 2012; Hensley and Kursula, 2016). Tubulin is the canonical binding partner of CRMP2. It has two isoforms, α and β, that usually form heterodimers. The dendritic spine contains abundant tubulin heterodimers. In the postsynaptic density (PSD, a structure just beneath the postsynaptic membrane), the amount of α-tubulin molecules accounts for 8% of the PSD protein mass, far exceeding the amount of PSD-95 molecules, which account for only ~ 0.8% (Yun-Hong et al., 2011). CRMP2 forms a tetramer in solution. Interaction with tubulin heterodimers breaks the tetramer of CRMP2 into monomers to form CABT complexes (Niwa et al., 2017).
At dendritic spines, the function of the CABT complex was largely unknown. Recent studies revealed that disruption of the CABT complex may cause spine loss as observed in Alzheimer's disease (more info). In schizophrenia, the spine density is also reduced (Glantz and Lewis, 2000). Strikingly, the gene encoding CRMP2, DPYSL2, is implicated in schizophrenia (Fallin et al., 2005; Pham et al., 2016).
In humans, GluN2B contains a long CTD, including residues 867 - 1484. In rats and mice, their CTD is only slightly shorter, starting from residue 867 to 1482. Both CRMP2 and tubulin have been shown to interact with the GluN2B subunit of NMDARs. The tubulin heterodimer may bind to the CTD of GluN2B at the region 1243 - 1376 (van Rossum et al., 1999). CRMP2 binds preferentially to GluN2B over GluN2A (Al-Hallaq et al., 2007). By utilizing a peptide array, Brittain et al. (2012) identified two peptides in GluN2B that may bind to CRMP2: peptide KPGMVFSISRGIYSC (residues 857–871 of the rat GluN2B sequence) and DWEDRSGGNFCRSCP (residues 1205–1219 of the rat GluN2B sequence). Notably, the second peptide contains the negatively charged sequence, DWED, which could interact with the positively charged H19 in CRMP2. Therefore, the CABT complex may bind to the CTD of GluN2B, with CRMP2's H19 near DWED (1205 - 1208) and the tubulin heterodimer around the region 1243 - 1376 (Figure 12-1).
The association between CABT and GluN2B could block NMDA currents (Figure 12-2), abolishing the NMDA plateau, consequently resulting in neuronal silence. With this function, CRMP2 is expected to play an important role in memory processing. Indeed, experiments have demonstrated that the antibody against CRMP2 causes amnesia (Mileusnic and Rose, 2011). Furthermore, memory extinction is impaired in schizophrenia (Holt et al., 2009; Holt et al., 2012).
The NMDAR blocked by CABT is a form of NMDAR desensitization, which is broadly defined as a reduction of NMDA currents in the continuous presence of glutamate. There are several mechanisms that may lead to NMDAR desensitization: Ca2+-dependent, glycine-dependent, glycine-independent, etc. (Thomas et al., 2006; Krupp et al., 2002; Tavalin and Colbran, 2017; Glasgow et al., 2017). To distinguish from other forms of desensitization, the NMDAR blocked by CABT will be called "NMDAR extinction", because it may give rise to the macroscopic memory extinction (inhibition of memory retrieval). Mounting evidence revealed that protein kinase A (PKA) could influence memory extinction (Koh et al., 2002; Isiegas et al., 2006; Mueller et al., 2008; Nijholt et al., 2008; Menezes et al., 2015). Therefore, the NMDAR extinction is likely dependent on PKA. Remarkably, the PKA-dependent NMDAR desensitization has indeed been observed (คาสิโนไทย). Further details are described in the next chapter.
Author: Frank Lee