|The Role of Microtubule Invasion into Spines||MT|
A previous article has shown that the level of tubulins at the postsynaptic density (PSD) may play an important role in epilepsy. This article will discuss the normal physiological process: how PSD is modified by synaptic stimulation. In particular, how tubulins and other plasticity-related proteins (PRPs) will enter only stimulated spines. The function of tubulins is not limited to their entry into spines. Their physiological role is even more important after they exit spines, which could explain synaptic reactivation and slow oscillations -- the two processes essential for memory consolidation.
Microtubule Invasion into Spines
In 2008, three independent labs demonstrated that microtubules could enter spines in an activity-dependent manner (reviewed in Dent et al., 2011). Upon synaptic stimulation, microtubules may polymerize all the way to PSD and, within 20 seconds to 30 minutes, depolymerize back to the dendritic shaft (Hu et al., 2008). The transient entry leads to thickening of PSD (Mitsuyama et al., 2008), suggesting that microtubule invasion may play a critical role in the assembly of PRPs into PSD.
PSD-95 is a scaffold protein responsible for the anchoring of AMPA receptors at the postsynaptic membrane. Synaptic stimulation may increase the level of both PSD-95 and AMPA receptors at the synapse. Recently, it has been shown that the BDNF-induced increase of PSD-95 in spines requires microtubule invasion. Further investigation indicated that microtubules did not transport PSD-95 into spines (Hu et al., 2011). Rather, microtubules could carry CaMKII into spines, and then capture diffusive PSD-95 and other PRPs, including tubulins.
In the sushi belt model (Doyle and Kiebler , 2011), microtubules were assumed to carry the mRNA of the CaMKII α-subunit into spines. However, recent studies have shown that upon synaptic stimulation CaMKII can bind to and decorate microtubules (Lemieux et al., 2012). Therefore, it is more likely that microtubules carry CaMKII proteins, than their mRNA.
According to this scenario, the major function of microtubule invasion is to deliver the "tag", CaMKII, for the capture of PRPs into the activated spines.
The late long-term potentiation (L-LTP) involves protein synthesis either from pre-existing mRNA near the synapse or from new mRNA transcribed in the cell body. The new mRNA or proteins produced in the cell body must then be delivered to the activated synapses. How do they know which synapses have been activated?
The synaptic tagging hypothesis (Frey and Morris, 1997) posits that activated synapses must be able to create a "tag" that can capture PRPs. Evidence suggests that CaMKII is the tag (Redondo et al., 2010). This is reasonable because, as mentioned in the previous article, the phosphorylated CaMKII interacts with diverse partners and controls the spine size. By contrast, knock-out of the PSD-95 gene affects mainly AMPA receptors, resulting in silent synapses which are located onto morphologically mature spines (Béïque et al., 2006).
The Role of Tubulins in PSD
Tubulins are highly negatively charged (Baker et al., 2001). They will make postsynaptic potential more hyperpolarized when they are captured into PSD by CaMKII. This has the inhibitory effects on neuronal excitability, similar to chloride ions. The inhibition by tubulins can prevent overexcitation. More importantly, the synapses could be "reactivated" when tubulins exit PSD, which is the topic of the next article.
Author: Frank Lee