|Tubulin Inhibition of NMDA Receptors in Dendritic Shaft||Memory|
NMDA receptors (NMDARs) are located not only at synapses, but also widely distributed in the extrasynaptic membrane. In particular, the spiny neurons of amygdala, striatum, and cerebral cortex are enriched with extrasynaptic NMDARs to produce NMDA plateaus that are crucial for the generation of action potentials. In the dentate gyrus (DG) of hippocampus, the extrasynaptic NMDARs also make significant contribution to neuronal firing, especially in young granule cells the action potential can be generated by NMDARs alone, without requiring AMPARs (Li et al., 2017). Hence, inhibition of NMDARs in the dendritic shaft can have significant impact on neuronal firing.
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 induced by the NMDA plateau may cause microtubule depolymerization to produce free tubulin, which in turn may bind and inhibit NMDARs. This provides a negative feedback to prevent excessive neuronal firing.
A singe DG granule cell receives inputs from 3600 to 5600 neurons in the entorhinal cortex. Yet more than 90% of DG neurons are silent. On the other hand, DG is located in a pathway that connects hippocampal regions with high propensity for generating seizures. This has led to the hypothesis that DG may serve as a control point for seizures in the hippocampus and that a breakdown of the dentate gate causes seizures (Lothman et al., 1992). Recent studies support the dentate gate hypothesis (Krook-Magnuson et al., 2015).
Seizures are characterized by intense neuronal firing, resulting in Ca2+ overload. In another article, the large amount of Ca2+ ions are proposed to terminate seizures by producing free tubulin to associate with the membrane at the axon initial segment. As discussed above, elevated Ca2+ level could also contribute to seizure termination by producing free tubulin to inhibit GluN2B-containing NMDARs in the dendritic shaft. This mechanism may account for epileptic amnesia, in which the main manifestation of seizures is recurrent episodes of amnesia (Butler and Zeman, 2008).
Lacosamide (LCM) is an antiepileptic drug. It has dual mechanism of action: enhancing the slow inactivation of voltage-gated sodium channels and modulating CRMP2. Exactly how LCM interacts with CRMP2 to exert its antiepileptic effect is not known. Normally, CRMP2 can bind with tubulin and also promote tubulin polymerization into a microtubule. However, the LCM-bound CRMP2 impairs tubulin polymerization without affecting its binding with tubulin (Wilson et al., 2014). As a result, the number of free tubulin/CRMP2 complexes increase which, according to the present model, should inhibit NMDARs, thereby suppressing neuronal firing.
Author: Frank Lee