8. Long-Term Potentiation
Long-term potentiation (LTP) refers to the long lasting enhancement of synaptic transmission. It is commonly divided into two phases: early phase (E-LTP) and late phase (L-LTP). E-LTP does not depend on new protein synthesis whereas L-LTP involves protein synthesis either from pre-existing mRNA near the synapse or from new mRNA transcribed in the cell body. Usually, L-LTP can be induced only by sufficiently strong stimulation.
The synaptic strength depends mainly on the number of AMPA receptors (AMPAR) at the synaptic site of a dendritic spine. An AMPAR is composed of four glutamate receptors, forming an ion channel that belongs to glutamate receptor ion channels (Traynelis et al., 2010). Each glutamate receptor is called a subunit. Four different subunits have been identified in AMPARs, designated as GluR1 - 4 (or GluA1 - 4). An AMPAR may be homomeric or heteromeric. In hippocampal neurons, the majority of AMPARs comprise GluR1/GluR2 or GluR2/GluR3 heteromers (Wenthold et al., 1996). Only about 8% are GluR1 homomers, which conducts both Na+ and Ca2+ ions. The presence of GluR2 makes AMPAR impermeable to Ca2+ ions (Man, 2011).
AMPARs can be activated by glutamate molecules released from the presynaptic axon terminal. Upon activation, the entry of permeable cations makes the postsynaptic membrane more depolarized, which facilitates excitation of the postsynaptic neuron. Therefore, synaptic transmission can be enhanced by increasing the number of AMPARs at the synapse.
During E-LTP, the Ca2+ influx through NMDA receptors (NMDARs) activates calcium/calmodulin-dependent protein kinase II (CaMKII) which drives AMPARs toward the synaptic site via two different routes (Henley et al., 2011):
E-LTP lasts only a couple of hours because AMPARs also continuously cycle into and out of synapses in a constitutive (activity-independent) manner. Recent studies suggest that the synaptic AMPARs added by LTP are GluR1 homomers, which are then replaced by GluR2-containing AMPARs located in the intracellular compartment. (Man, 2011).
Figure 8-2. AMPAR trafficking during early LTP. [Image source: Wikipedia]
Long-term depression (LTD) results from the decrease in the number of synaptic AMPARs via endocytosis (Henley et al., 2011, Figure 2). Interestingly, both LTP and LTD can be induced by Ca2+ influx. It has been found that the selective induction of LTP or LTD depends on Ca2+ elevation patterns. A brief increase of intracellular Ca2+ with relatively high magnitude induces LTP while a prolonged modest rise of intracellular Ca2+ induces LTD (Yang et al., 1999).
Late LTP and Synaptic Tagging
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 plasticity-related proteins (PRPs) for the maintenance of LTP. Evidence suggests that CaMKII is the tag (Redondo et al., 2010). This is consistent with the findings that activated (phosphorylated) CaMKII interacts with diverse partners and controls the spine size. (Yoshimura et al., 2000; Pi et al., 2010). The activation of CaMKII is known to promote its association with postsynaptic density (PSD) - a protein complex located underneath the postsynaptic membrane of the spine. Inactivation will cause CaMKII to gradually exit PSD (Yoshimura and Yamauchi, 1997).
Synaptic activation by strong stimulation or BDNF may cause more CaMKII to enter spines via microtubules. In 2008, three independent labs demonstrated that microtubules could enter spines in an activity-dependent manner (reviewed in Dent et al., 2011). Upon 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. Recent studies have shown that upon synaptic stimulation CaMKII can bind to and decorate microtubules (Lemieux et al., 2012).