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", comprises 100 presynaptic stimulations at high frequencies (~100 Hz). This leads to NMDAR-dependent potentiation as monitored by field excitatory postsynaptic potentials (f-EPSPs). In most cases, the time course of f-EPSP consists of two phases: a transient decaying phase known as short-term potentiation (STP), followed by a stable LTP (Figure 14-1).

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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 (open squares) completely abolishes LTP.
(C) 10 μM UBP145 (filled triangles) reduces STP but spares LTP.
[Source: France et al., 2017]

The origin of STP is not known. Several lines of evidence suggest that it could result from the inhibition of NR2B-containing NMDARs by tubulin and CRMP2 (Chapter 7).

  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 NR2B-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 NR2B-containing NMDARs (Volianskis et al., 2013; Park et al., 2013).
  3. The number of microtubule invasions into spines per hour is about 3, i.e., 1 spine every 20 minutes (Hu et al., 2008), which is in the same order of magnitude as the decay time of STP.

Experimental studies further showed that STP2 is also sensitive to UBP145, which specifically targets GluN2D-containing NMDARs. Therefore, both tubulin and CRMP2 could also bind to GluN2D (NR2D).

 

Author: Frank Lee
First Published: November, 2017