|Memory Consolidation: Tubulins Calling the Shots||Memory|
Memory consolidation is a process that selectively converts some labile memory traces into long-term memory (LTM). It occurs mainly during sleep. This chapter is focused on memory consolidation in the neocortex. Similar mechanisms may apply to the hippocampus and amygdala, which are discussed in Chapter 12.
The protein kinase C (PKC) plays a central role in long-term memory by regulating both microtubule tracks (MTTs) and protein synthesis (see Chapter 7). Therefore, memory consolidation should involve PKC activation. The following sections will explain how the communication between hippocampus and neocortex during sleep can lead to PKC activation only around the neocortical synapses which have been strongly activated while awake.
Signaling Cascade Originating in Neocortex
The spontaneous synaptic reactivation (see Chapter 8) will cause Ca2+ entry into spines through NMDAR and other Ca2+-conducting channels. If the reactivation is sufficiently strong, these Ca2+ ions may cause Ca2+ release from the spine apparatus (an endoplasmic reticulum at the spine) by activating ryanodine receptors which are a special type of Ca2+ channels that can also be activated by ryanodine. This process is called the calcium-induced calcium release.
The large amount of Ca2+ ions released from the spine apparatus are essential for the association between tubulins and the plasma membrane. This can prevent construction of aberrant microtubule tracks. The tubulins which exit from spines into the dendritic shaft should be polymerized only under the regulation of PKC, that is, after PKC is activated by signals from the hippocampus.
The association between tubulins and the plasma membrane could be the origin of the DOWN state observed in slow wave sleep.
The DOWN State
The DOWN state is characterized by hyperpolarization which is related to the postburst slow afterhyperpolarization (sAHP) (Buzsáki et al., 2012). It has been known for many years that Ca2+ ions are required for sAHP, and the hyperpolarization in both DOWN state and sAHP is caused by outward K+ currents (Timofeev et al., 2001; Andrade et al., 2012). At first, researchers were trying to identify the putative "Ca2+-activated K+ channels" responsible for sAHP, but to no avail. Only recently has it been realized that the dependence of sAHP-related K+ currents on Ca2+ is indirect. Moreover, sAHP arises from a wide variety of K+ channels, rather than any single type of K+ channels. It has been found that the stability of most K+ channels requires binding with a membrane phospholipid known as PIP2 [or PtdIns(4,5)P2] (Andrade et al., 2012). Incidentally, the major pathway to activate PKC is the hydrolysis of PIP2, producing IP3 and DAG (diacylglycerol).
Available evidence suggests that there exists a neuronal calcium sensor (NCS) which, together with Ca2+, can enhance the binding between PIP2 and K+ channels, thereby increasing the outward K+ currents (Andrade et al., 2012, Figure 3). Although the calcium-binding protein, hippocalcin, is a possible NCS, the sAHP was not completely eliminated in the hippocalcin knockout mouse. Furthermore, the distribution of hippocalcin in the brain only partly overlaps with the distribution of neurons exhibiting a pronounced sAHP (Andrade et al., 2012). Could tubulin be the Ca2+ partner?
Most membrane phospholipids are negatively charged, which would repel the negatively charged tubulin. Therefore, tubulin cannot associate with the membrane unless there is a special interaction. The positive Ca2+ ions may provide the special interaction by serving as an adaptor connecting the tubulin with the membrane. On the other hand, tubulin can also bind to PIP2 through a specific interaction. The interaction among tubulin, PIP2 and the G protein subunit, Gαq, has been shown to regulate the activation of phospholipase C (PLC) - the enzyme which catalyzes the hydrolysis of PIP2 (Popova et al., 1997; Popova et al., 2002).
Signaling Induced by Hippocampus
The sharp wave ripples generated in the hippocampus will travel along brain circuits to the neocortex. When they arrive at the neocortical nerve terminals, they will induce glutamate release. The terminals stimulated more frequently will release larger amount of glutamates. The glutamate receptor responsible for the activation of PKC is mGluR, which belongs to G-protein-coupled receptors (see Chapter 6). Upon activation by glutamate, mGluR causes Gα to interact with its effector PLC. The activated PLC can then catalyze PIP2 hydrolysis, producing IP3 and DAG. PKC is activated by DAG (Figure 10-2).
mGluR has several subtypes. The most important one involved in memory consolidation could be mGluR1, which is coupled to Gαq. More importantly, mGluR1 is concentrated in perisynaptic and extrasynaptic areas, not at the postsynaptic membrane (Ménard and Quirion, 2012). Therefore, only the glutamates that can diffuse to these areas may activate mGluR1. This ensures that only strongly stimulated terminals can activate PKC. Hence, MTTs will be modified only around the neocortical spines which are reactivated strongly and stimulated robustly by signals from the hippocampus.
Author: Frank Lee