|Forgetting by CaMKII Inhibition||Memory|
Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays central roles in synaptic plasticity. It belongs to a class of enzymes called protein kinase which catalyzes phosphorylation - addition of a phosphate group (PO43-) to a protein. In cells, phosphorylation is widely used to regulate protein structure and function.
CaMKII is the major target of Ca2+ ions which enter spines during long-term potentiation (LTP). The transient Ca2+ influx leads to persistent activation of CaMKII (Figure 5-1). The activated CaMKII promotes its association with postsynaptic density (PSD) by interacting with NMDAR (Yoshimura and Yamauchi, 1997; Bayer et al., 2001). Subsequently, CaMKII can induce the insertion of AMPARs into the postsynaptic membrane, thereby enhancing the synaptic strength.
CaMKII Entry Into Spines
In the absence of stimulation, a small amount of CaMKII may enter spines through interaction with PSD-95, which is a scaffold protein capable of coordinating with other plasticity-related proteins (PRPs) to form a synapse (Keith and El-Husseini, 2008; Mogha et al., 2012). Upon stimulation that induces LTP, the CaMKII diffusing randomly in the dendritic shaft may be carried into activated spines by microtubules (more info). The increase of CaMKII in the activated spine can then capture other PRPs, such as PSD-95 (Hu et al., 2011), which further enlarges the spine size and enhances the synaptic strength.
Like the AMPAR insertion into the postsynaptic membrane, other memory traces associated with LTP-induced CaMKII entry into spines are short lived. Neurons contain a basal level of phosphatase that can dephosphorylate and inactivate CaMKII. Furthermore, there is a CaMKII inhibitor (CaMKIIN) which has been shown to depress synaptic strength by disrupting the binding between CaMKII and NMDAR (Gouet et al., 2012). CaMKIIN is constitutively active. Once CaMKIIN is produced, it will cause CaMKII to gradually exit spines, followed by other PRPs which were captured during LTP induction. CaMKIIN increases rapidly in the hippocampus and amygdala after learning (Gouet et al., 2012). The CaMKII inhibitor is also upregulated significantly in the cerebral cortex during sleep (Chiara Cirelli, personal communication).
Thus, both AMPAR endocytosis and CaMKII inhibition are constantly erasing memory traces at the spines. Constitutive memory erasure is beneficial for the brain when trivial memories are eliminated, but how can important memories be retained? The mechanism for the formation of long-term memory will be discussed in subsequent chapters.
Author: Frank Lee