|Time Heals: The Role of BDNF in Memory Extinction||Memory|
Memories will normally fade away with time regardless of whether they are tragic incidents or joyful events. From the studies of dendritic plateau potentials produced in a dendritic branch and the finding that the dendritic branch, rather than individual synapses, is the preferred memory unit, the previous chapter arrives at the following conclusion: the more NMDARs in the same branch are inhibited, the harder the memory involving this branch will be retrieved. Both tubulin and CRMP2 bind only to NR2B, not NR2A. Therefore, the fact that memories fade away with time suggests that the amount of inhibited NR2B-containing NMDARs should increase as we age. A growing number of studies have revealed that this natural process is mainly governed by the brain-derived neurotrophic factor (BDNF).
The Medial Prefrontal Cortex
The medial prefrontal cortex (mPFC) has been demonstrated to play a key role in memory extinction (Peters et al., 2009). Anatomically, PFC is located in the anterior pole of the frontal cortex, including the anterior cingulate cortex (ACC), mPFC, and orbital frontal cortex (OFC). In rodents (e.g., rats and mice), mPFC can be further subdivided into prelimbic and infralimbic cortexes, corresponding to dorsal and ventral regions, respectively (Figure 12-1). The infralimbic cortex is implicated in fear extinction (Sotres-Bayon et al., 2009; Rosas-Vidal et al., 2014) whereas the prelimbic cortex seems to be more involved in drug seeking (Gass and Chandler, 2013).
Intriguingly, mPFC is the region that initiates slow oscillations (Nir et al., 2011) which have been shown to orchestrate memory consolidation during sleep (Mölle and Born 2011). Memory consolidation refers to a process that converts short term memory into long-lasting storage. Its underlying mechanism is largely unknown. Even the engram of the very long-term memory (> 1 month) remains elusive. This book will propose that the very long-term memory is stored in microtubule tracks. Thus, memory consolidation should involve the construction of microtubule tracks. Very interestingly, CRMP2 happens to play a pivotal role in microtubule polymerization and dendritic branching (Hensley and Kursula, 2016; Niisato et al., 2013). Therefore, the following simple mechanism of memory consolidation is emerging: as tubulin and CRMP2 dissociate from NR2B-containing NMDARs, they may trigger slow oscillations and direct the construction of microtubule tracks for long-lasting memory. Further details are discussed in later chapters.
BDNF: the Molecule of Memory Extinction
BDNF infused into the infralimbic cortex is capable of inducing fear extinction (Peters et al., 2010). Infusion of BDNF into the dorsal mPFC attenuates reinstatement to cocaine-seeking behavior (Berglind et al., 2009), suggesting that the memory of cocaine-induced pleasure could be suppressed by BDNF. Furthermore, hippocampal-specific deletion of the BDNF gene significantly reduced extinction of conditioned fear (Heldt et al., 2007). Therefore, BDNF in both mPFC and hippocampus has the capacity to cause memory extinction. Recent studies have provided great insights into its mechanism.
In the C-terminal domain of the NR2B subunit, there are three tyrosine residues (abbreviation: Y) which can be phosphorylated by Fyn or Src kinase. Phosphorylation at Y1472 prevents NR2B-containing NMDARs from being internalized (Chen and Roche, 2007), consequently increasing their localization to the membrane. The membrane-bound NR2B-containing NMDARs are subject to tubulin inhibition, which would hinder the generation of action potentials via NMDA spikes and dendritic plateau potentials (Chapter 11). BDNF has been shown to promote Y1472 phosphorylation (Xu et al., 2006), possibly through the BDNF/TrkB/Akt/Girdin/Src pathway (Nakai et al., 2014). This notion is supported by the finding that the Src family kinases are involved in the BDNF-mediated suppression of cocaine-seeking (Barry and McGinty, 2017).
Tet1 also plays an important role in memory extinction (Rudenko et al., 2013), but its actions could be mediated by BDNF. Tet1 is an enzyme that promotes DNA demethylation which is often used to regulate gene expression. Tet1 has been demonstrated to regulate the expression of the BDNF gene (Hsieh et al., 2016; Keifer, 2017).
Tubulin binds only to NR2B, not NR2A. As time goes by, most NR2B-containing NMDARs will be inhibited by tubulin. The dendritic branch enriched with NR2B-containing NMDARs would hinder the generation of action potentials and the memory involving this branch would be more likely to become extinct. The extinction memory can be retrieved only by specific stimuli (to be discussed in later chapters).
In cortical neurons, both NR2A and NR2B increase with age. In the hippocampus, however, NR2A increases whereas NR2B declines with age (Dong et al., 2006). The NR2B-NR2A switch has been proposed to underlie the mechanism of infantile amnesia - the inability of adults to recall events from early childhood (Travaglia et al., 2016). This hypothesis is consistent with the Tubulin Inhibition Model for memory extinction. At early childhood, NR2B dominates in both cortical and hippocampal neurons. Therefore, the childhood memories should be encoded predominately by the neurons enriched with NR2B-containing NMDARs. These memories would become very hard to retrieve due to the gradual inhibition by tubulin. As we grow older, more NR2A-containing NMDARs are produced. Since tubulin does not bind to NR2A, the NR2A-containing NMDARs will never be inhibited by tubulin so that they can facilitate the generation of action potentials via NMDA spikes and dendritic plateau potentials (Chapter 11).
Author: Frank Lee