Geon Tubulin Inhibition: Evidence from Short Term Potentiation Memory

 

Experimentally, long-term potentiation (LTP) can be induced by several different protocols (Shipton and Paulsen, 2013, Table 1). One of them, referred to as "tetanus", applies high frequency (~100 Hz) stimulation on the presynaptic neuron for about 1 second. This leads to postsynaptic potentiation as monitored by field excitatory postsynaptic potentials (f-EPSPs). In most cases, the time course of f-EPSP consists of two phases: an initial decaying phase and a stable phase (Figure 14-1). LTP refers to the stable phase while the initial decaying phase is known as short-term potentiation (STP) (Volianskis et al., 2013; Park et al., 2013).

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Figure 14-1. The time course of potentiation as manifested by f-EPSP.
(A) Tetanic stimulation induced both STP and LTP (open circles). The antagonist D-AP5 (filled circles) blocks the induction of STP and LTP; 0.1 μM NVP (open triangles) has no effect on the induction of potentiation whereas 1 μM NVP blocks both STP and LTP (filled triangles).
(B) STP is significantly reduced after pre-incubation with 1 μM Ro 25-6981 (filled squares) whereas LTP is not affected. 10 μM Ro 25-6981 (open squares) completely abolishes LTP.
(C) 10 μM UBP145 (filled triangles) reduces STP but spares LTP.

NVP, Ro 25-6981 and UBP145 target GluN2A-, 2B- and 2D-containing NMDARs respectively. D-AP5 is a non-selective NMDAR antagonist.
[Source: France et al., 2017]

The mechanism of STP is not known. Several lines of evidence suggest that it could result from the inhibition of GluN2B-containing NMDARs by tubulin and CRMP2 (Chapter 7), while the GluN2A-containing NMDARs were not affected, contributing to the sustained phase of f-EPSPs (i.e., LTP).

  1. The tetanic stimulation used to induce LTP has been demonstrated to cause microtubule invasion into spines (Mitsuyama et al., 2008), which may carry tubulin and CRMP2 into spines to inhibit GluN2B-containing NMDARs at the synapse (Chapter 10).
  2. STP can be separated into two pharmacologically and kinetically distinct components: STP1 and STP2. STP2 decays more slowly than STP1. Pharmacologically, STP1 is similar to LTP, but STP2 can be abolished by Ro 25-6981, which selectively inhibits GluN2B-containing NMDARs (Volianskis et al., 2013; Park et al., 2013).
  3. The time for microtubules to invade spines takes minutes (Hu et al., 2008), which is approximately the same as the duration of STP.

This hypothesis predicts that both tubulin and CRMP2 could also bind to GluN2D (NR2D), as STP is also sensitive to the GluN2D-selective antagonist UBP145.

 

Author: Frank Lee
First Published: November, 2017