Web Box 8.1 The Cutting Edge: Late-LTP, Learning, and Memory

Long-term potentiation (LTP) is the prevailing model for relating synaptic plasticity to learning and memory. However, if we try to link this process to long-term information storage in the brain, it quickly becomes apparent that E-LTP suffers from the significant limitation that it lasts only a few hours at most. Yet we all know from experience that memories can last a lifetime. Therefore, we need a process that strengthens synaptic connections for a significantly longer period of time than E-LTP, which leads us to L-LTP.

How is L-LTP produced, and how does it differ from E-LTP? First, we need much stronger presynaptic (tetanic) stimulation. For example, some L-LTP studies utilize four bursts of electrical stimuli instead of the single stimulus burst required for E-LTP. Second, we know that L-LTP (unlike E-LTP) requires protein synthesis, since the administration of a protein synthesis inhibitor blocks L-LTP production. This is an important distinction because numerous animal studies have shown that memory consolidation (the formation of a long-term memory store) also requires protein synthesis (Wang and Morris, 2010). Third, we already mentioned a role for BDNF in E-LTP, but this growth factor may be even more important in the mechanisms of L-LTP. In contrast to the fragile X mental retardation protein described in Box 8.1 in the main text, which inhibits local dendritic protein synthesis, BDNF facilitates this process. Changes in postsynaptic protein expression mediated by BDNF appear to be necessary for L-LTP to occur (Leal et al., 2017). Fourth, L-LTP is characterized by structural changes in the affected dendrite, including the formation of new dendritic spines that accompanies the enlargement of preexisting ones (Bosch and Hayashi, 2012; Chidambaram et al., 2019) (Figure 1). As we already mentioned, spine enlargement also occurs in E-LTP to make space for the added AMPA receptors; however, L-LTP ensures that dendritic spine growth is stabilized beyond just a few hours.

One additional factor that has been a topic of controversy in recent years is the potential role in L-LTP of an unusual form of protein kinase C (PKC) known as protein kinase M-zeta (PKMζ). Dendritic synthesis of this enzyme is repressed under baseline conditions, but the synthesis can be de-repressed by strong synaptic activity (e.g., activity induced by tetanic stimulation). Once expressed, PKMζ remains active until it is either turned off or metabolized. Various laboratories have performed elegant experiments implicating either CaMKII or PKMζ as a (the?) key molecule required for L-LTP and long-term memory storage, which has given rise to the controversy. These studies and their interpretation are presented in a series of papers published several years ago (Lisman, 2017; Bear et al., 2018; Sacktor and Fenton, 2018). At the present time, neither side has won out. But this should not be discouraging. As stated in an earlier commentary by Frankland and Josselyn (2013), “Given evolution’s penchant for redundancy, it seems unlikely that any single molecule will play this part [the mediation of long-term memory storage] solo” (p. 313). Thus, the neuroscience community may ultimately conclude that both CaMKII and PKMζ participate significantly in the memory storage process.

Up to now, we have only discussed the existence of LTP in animals or in brain slices. An obvious key question is whether LTP also occurs in humans, and if so, how important it is for memory encoding and storage. It is easy to see why this question may be difficult to address, not only because we don’t have ready access to human brain tissue for study but also because the tetanic stimuli typically used to induce LTP do not represent a common firing pattern in the brain. Fortunately, we have some relevant information on this issue resulting from the discovery of theta burst LTP (Larson and Munkácsy, 2015). This form of LTP has mechanisms similar to those discussed earlier, but instead of being induced by one or more long (1-second) stimulus bursts, it is induced by several short bursts separated by 5- to 10-second intervals. Importantly, this frequency interval has biological relevance because it corresponds to the theta rhythm seen in EEG recordings of the hippocampus as well as other brain areas. Up to now, for technical reasons the ability of theta burst stimulation to produce plasticity in the human brain has mainly been studied in parts of the neocortex, particularly the primary motor cortex M1 (Suppa et al., 2016). Despite this difference from typical animal studies, the results support the idea that an LTP-like form of neural plasticity can be evoked by theta burst stimulation in humans. This plasticity takes the form of increased neural excitability that, like E-LTP, endures for more than 60 minutes and is dependent on NMDA receptor activation (Huang et al., 2005; 2007; Teo et al., 2007). Researchers further assume the existence of an L-LTP–like process in the human brain, although such a process has not yet been proven because of the daunting experimental challenges.

Cognitive psychologists and neuroscientists have long known of the existence of several different types of memory categorized by the types of information they encode and the length of information storage. Richard Morris and some other researchers in this field argue that NMDA receptor-dependent LTP or other kinds of synaptic plasticity primarily mediate the encoding of episodic-like memories (i.e., memories of specific events and experiences; Morris, 2013; Takeuchi et al., 2014; but see Taylor et al., 2014, for an opposing view). As discussed above, the relationship between LTP and learning/memory has been studied most extensively in the hippocampus, particularly with respect to the learning of spatial tasks. However, LTP occurs in other brain areas as well, and this process has been linked to the learning of other kinds of tasks mediated by the amygdala (e.g., fear conditioning), striatum (e.g., motor learning), and pyriform cortex (e.g., olfactory association learning) (Morris, 2013). Because the synaptic plasticity produced by LTP consists of changes in “synaptic weights” (the strength of synaptic connections within neuronal networks), researchers have proposed various tests to challenge the theory that such changes are necessary and sufficient to encode memory. As summarized by Abraham and coworkers (2019), numerous experiments invoking these tests appear to support the theory; however, alternative theories cannot yet be ruled out. For example, Smolen and colleagues (2019) recently proposed that some type of positive feedback loop may be necessary for maintaining memories for extremely long time periods.

Last but certainly not least, it’s important to be aware that the hippocampus is only crucial for initial memory encoding. According to current theories, information is initially encoded and stored by a network of connections within and between the hippocampus and the neocortex (Squire et al., 2015). Over time, the hippocampus further organizes the memory encoding within the cortex, strengthening certain network connections and weakening others (a process called memory consolidation). Eventually, retrieval of the memory is largely independent of the hippocampus (Figure 2). This is illustrated by the observation that although H.M. was unable to form new memories, he could still recall many events that had occurred prior to the loss of his hippocampus. One of the key remaining challenges for neuroscientists is to determine the mechanisms, both in animals and humans, by which memory consolidation occurs.

References

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