|The Extinction State of NMDA Receptors||Memory|
In the dentate gyrus, 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 (Barth and Poulet, 2012), and other subregions of the hippocampus (Thompson and Best, 1989). What causes these cells to become silent?
In the spiny neurons of memory storage areas, 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 first (see Chapter 10). In silent cells, the NMDA receptors (NMDARs) may somehow be inhibited so that they are unable to produce NMDA plateau. This chapter shows that NMDARs could be inhibited by tubulin.
Tubulin is the building block of microtubules. It has been demonstrated to interacts with NMDARs, specifically at the cytoplasmic domain of GluN1 (formerly NR1) and GluN2B (NR2B) subunits (van Rossum et al., 1999). The opening of NMDARs requires both glutamate binding and the relief of Mg2+ block. The latter depends on electric fields. During associative learning, the Mg2+ block is relieved by the membrane potential field when the postsynaptic neuron fires. However, the binding of tubulin to NMDARs may hinder Mg2+ relief. Tubulin has two isoforms, α and β, that usually form heterodimers. In a tubulin heterodimer, the number of negatively charged amino acids exceeds that of positively charged amino acids by about 50 (Minoura and Muto, 2006). Hence, tubulin is a highly negatively charged molecule. It can produce an inward electric field to counteract the outward depolarizing field, thereby inhibiting the relief of Mg2+ block (Figure 11-1).
The interaction between NMDAR and tubulin alone is likely to be weak, as the amount of tubulin in the postsynaptic density (PSD) increases if the isolated brain slice has been kept on ice for longer period, but decreases if the isolated PSD sample is washed with detergent-containing solutions (Yun-Hong et al., 2011). Interestingly, tubulin is the canonical binding partner of collapsin response mediator protein 2 (CRMP2) (Fukata et al., 2002), which also interacts with GluN2B (Al-Hallaq et al., 2007; Brustovetsky et al., 2014). Therefore, CRMP2/tubulin may associate tightly with GluN2B to impede the opening of NMDARs, 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).
The NMDAR inhibited by tubulin will be called the "extinction state", as it can give rise to the macroscopic memory extinction. Biophysically, the extinction state of an NMDAR resembles the inactivated state of a sodium channel (Yu and Catterall, 2003).
Author: Frank Lee