|Memory Extinction: Inhibition of NMDARs in Dendritic Shaft||Memory|
Trivial memories, those induced by weak stimulation, are usually erased in a few hours through constitutive AMPAR endocytosis. Strong stimulation, such as a traffic accident or sexual assault, may linger on much longer. The memories induced by strong stimulation do not go away abruptly. Instead, they fade away as time goes by. That means, memory extinction is not an "all-or-none" process. It is decremental. If memory extinction is due to NMDAR inhibition by tubulin as proposed in Chapter 7, this implies that the number of inhibited NMDARs increases with time. More inhibited NMDARs will make the memory harder to recall.
NMDARs are not restricted to synapses. They are also widely distributed in the extrasynaptic membrane. In particular, the spiny neurons (Figure 11-1) of amygdala, striatum, and cerebral cortex are enriched with extrasynaptic NMDARs to produce NMDA spikes (Chapter 7) and dendritic plateau potentials (Figure 11-2) that are crucial for the generation of action potentials. Inhibition of these NMDARs by tubulin could lead to memory extinction.
Both NMDA spikes and dendritic plateau potentials arise from the opening of NMDARs. The latter engages more NMDARs (Figure 11-3). It could even include most NMDARs in the entire dendritic branch. NMDARs are permeable to Ca2+ ions. Thus, the dendritic plateau potential will induce large Ca2+ influx. It has been well established that Ca2+ ions promote microtubule depolymerization (O'Brien et al., 1997; Lefèvre et al., 2011). Therefore, the elevated Ca2+ concentration may cause microtubule depolymerization to produce free tubulin, which in turn may bind and inhibit NMDARs. The dendritic branch, rather than individual synapses, is the preferred memory unit (Govindarajan et al., 2011). Hence, the more NMDARs in the same branch are inhibited, the harder the memory involving this branch will be retrieved.
Since both tubulin and CRMP2 bind only to NR2B, not NR2A, the above mechanism should inhibit only NR2B-containing NMDARs. This prediction agrees with the finding that in adult cortex the activation of NR2B-containing NMDARs triggers long-term depression (LTD) whereas long-term potentiation (LTP) requires activation of NR2A-containing NMDARs (Massey et al., 2004).
Seizures are characterized by intense neuronal firing, resulting in Ca2+ overload. In another article, the large amount of Ca2+ ions is proposed to terminate seizures by producing free tubulin to associate with the membrane at the axon initial segment. As discussed above, elevated Ca2+ could also contribute to seizure termination by producing free tubulin to inhibit NR2B-containing NMDARs. This mechanism may account for epileptic amnesia, in which the main manifestation of seizures is recurrent episodes of amnesia (Butler and Zeman, 2008).
Author: Frank Lee