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, there is substantial evidence that a neuropeptide called brain-derived neurotrophic factor (BDNF) is released by the tetanic stimulus and plays a key role in L-LTP. In contrast to the fragile X mental retardation protein described in textbook Box 8.1, which inhibits local dendritic protein synthesis, BDNF facilitates this process. Changes in postsynaptic protein expression mediated by BDNF are thought to be necessary for L-LTP to occur (Panja and Bramham, 2014; Leal et al., 2015). Fourth, L-LTP is characterized by structural changes in the affected dendrite, including the formation of new dendritic spines and the enlargement of preexisting spines (De Roo et al., 2008; Bosch and Hayashi, 2012). Spine enlargement also occurs in E-LTP, presumably to make space for the added AMPA receptors; however, L-LTP ensures that dendritic spine growth is stabilized beyond just a few hours. Finally, several additional biochemical mechanisms besides BDNF release are thought to be involved in both the structural changes just mentioned and the stabilization of the extra AMPA receptors that have been added to the membrane. One hypothesis is that atypical (uncommon) forms of protein kinase C (PKC) play a key role in L-LTP and in memory retention by inhibiting AMPA receptor endocytosis (removal of the receptors from the cell membrane) (Jalil et al., 2015). In support of this hypothesis, inhibition of one of these atypical PKCs, called protein kinase Mzeta, caused increased AMPA receptor endocytosis, prevented L-LTP from occurring, and impaired spatial memory in rats (Dong et al., 2015). When a different experimental approach was used to reduce the rate of AMPA receptor endocytosis, memory retention was improved both in normal rats and in a transgenic mouse model of Alzheimer’s disease. If confirmed in future studies, these findings raise the intriguing possibility of a new therapeutic target for patients with Alzheimer’s disease and other disorders involving cognitive impairment.

The discussion above shows that researchers have made immense progress in understanding the mechanisms underlying LTP and, to a lesser extent, the relationship between LTP and memory. Nonetheless, areas of uncertainty remain. For example, although there is near complete agreement that LTP at the CA1 Schaffer collateral synapses requires postsynaptic changes (e.g., an increase in AMPA receptors in the dendritic spine membrane), some investigators believe that these postsynaptic changes are entirely responsible for LTP at the affected synapses (Nicoll and Roche, 2013; Granger and Nicoll, 2014), whereas others argue that presynaptic changes, such as an increase in the probability of glutamate release from the nerve terminals, may also occur (Bliss and Collingridge, 2013; Park et al., 2014). There is some evidence that differing pre- and postsynaptic forms of LTP can occur at the same population of synapses, depending on the stimulation parameters (Padamsey and Emptage, 2014; Park et al., 2014); however, it is unsettling that this controversy remains unresolved so many years after the discovery of LTP. Another key question is whether LTP occurs in humans, and if so, how important is it for memory consolidation? It is easy to see why this question may be difficult to address, first because the majority of LTP studies are performed in vitro using brain slices or cells obtained from experimental animals, and second 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, the ability of theta burst stimulation to produce plasticity in the human brain has mainly been studied in parts of the neocortex, instead of the hippocampus, for technical reasons. 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 (Córdoba-Montoya et al., 2010; Suppa et al., 2016). There is even some evidence for an involvement of NMDA receptors in this plasticity. Yet, it is clear that much more research is required before we can be confident that the processes of LTP and LTD demonstrated in rats and mice accurately model the types of synaptic plasticity that occur in people when we form new memories or forget old ones.

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 receptors, operating through 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). Although there remain challenges and areas of contention regarding the exact relationship between NMDA receptor–mediated LTP and behavior, this is still one of the best, if not the best, models for understanding the cellular mechanisms of memory encoding. Note that, like Morris, we are emphasizing a role for LTP in the encoding of information by the hippocampus and other brain areas mentioned. Long-term memory storage is independent of LTP and is believed, instead, to be mediated by broadly distributed neural networks within the neocortex and connecting the cortex with key subcortical structures (see Chklovskii et al., 2004; Jung et al., 2008; Hofer, 2010; Insel and Takehara-Nishiuchi, 2013).

 

References

Bliss, T. V. P., and Collingridge, G. L. (2013). Expression of NMDA receptordependent LTP in the hippocampus: Bridging the divide. Mol. Brain, 6, 5. doi: 10.1186/1756-6606-6-5.

Bosch, M., and Hayashi, Y. (2012). Structural plasticity of dendritic spines. Curr. Opin. Neurobiol., 22, 383–388.

Chklovskii, D. B., Mel, B. W., and Svoboda, K. (2004). Cortical rewiring and information storage. Nature, 431, 782–788.

Córdoba-Montoya, D. A., Albert, J., and López-Martin, S. (2010). All together now: Long term potentiation in the human cortex. Rev. Neurol., 51, 367–374.

De Roo, M., Klauser, P., Mendez Garcia, P., Poglia, L., and Muller, D. (2008). Spine dynamics and synapse remodeling during LTP and memory processes. Prog. Brain Res., 169, 199–207.

Dong, Z., Han, H., Li, H., Bai, Y., Wang, W., Tu, M., et al. (2015). Long-term potentiation decay and memory loss are mediated by AMPAR endocytosis. J. Clin. Invest., 125, 234–247.

Granger, A. J., and Nicoll, R. A. (2014). Expression mechanisms underlying longterm potentiation: A postsynaptic view, 10 years on. Philos. Trans. R. Soc. Lond. B Biol. Sci., 369, 20130136. doi: 10.1098/rstb.2013.0136.

Hofer, S. B. (2010). Structural traces of past experience in the cerebral cortex. J. Mol. Med. (Berl.), 88, 235–239.

Insel, N., and Takehara-Nishiuchi, K. (2013). The cortical structure of consolidated memory: A hypothesis on the role of the cingulate-entorhinal cortical connection. Neurobiol. Learn. Mem., 106, 343–350.

Jalil, S. J., Sacktor, T. C., and Shouval, H. Z. (2015). Atypical PKCs in memory maintenance: The roles of feedback and redundancy. Learn. Mem., 22, 344–353.

Jung, M. W., Baeg, E. H., Kim, M. J., Kim, Y. B., and Kim, J. J. (2008). Plasticity and memory in the prefrontal cortex. Rev. Neurosci., 19, 29–46.

Larson, J., and Munkácsy, E. (2015). Thetaburst LTP. Brain Res., 1621, 38–50.

Leal, G., Afonso, P. M., Salazar, I. L., and Duarte, C. B. (2015). Regulation of hippocampal synaptic plasticity by BNDF. Brain Res., 1621, 82–101.

Morris, R. G. M. (2013). NMDA receptors and memory encoding. Neuropharmacology, 74, 32–40.

Nicoll, R. A., and Roche, K. W. (2013). Long-term potentiation: Peeling the onion. Neuropharmacology, 74, 18–22.

Padamsey, Z., and Emptage, N. (2014). Two sides to long-term potentiation: A view towards reconciliation. Philos. Trans. R. Soc. Lond. B Biol. Sci., 369, 20130154. doi: 10.1098/rstb.2013.0154.

Panja, D., and Bramham, C. R. (2014). BDNF mechanisms in late LTP formation: A synthesis and breakdown. Neuropharmacology, 76, 664–676.

Park, P., Volianskis, A., Sanderson, T. M., Bortolotto, Z. A., Jane, D. E., Zhuo, M., et al. (2014). NMDA receptor-dependent long-term potentiation comprises a family of temporally overlapping forms of synaptic plasticity that are induced by different patterns of stimulation. Philos. Trans. R. Soc. Lond. B Biol. Sci., 369, 20130131. doi: 10.1098/rstb.2013.0131.

Suppa, A., Huang, Y.-Z., Funke, K., Ridding, M. C., Cheeran, B., Di Lazzaro, V., et al. (2016). Ten years of theta burst stimulation in humans: Established knowledge, unknowns and prospects. Brain Stimul., 9, 323–335.

Takeuchi, T., Duszkiewicz, A. J., and Morris, R. G. M. (2014). The synaptic plasticity and memory hypothesis: Encoding, storage and persistence. Philos. Trans. R. Soc. Lond. B Biol. Sci., 369, 20130288. doi: 10.1098/rstb.2013.0288.

Taylor, A. M., Bus, T., Sprengel, R., Seeburg, P. H., Rawlins, J. N. P., and Bannerman, D. M. (2014). Hippocampal NMDA receptors are important for behavioral inhibition but not for encoding associative spatial memories. Philos. Trans. R. Soc. Lond. B Biol. Sci., 369, 20130149. doi: 10.1098/rstb.2013.0149.

Wang, S.-H., and Morris, R. G. M. (2010). Hippocampal-neocortical interactions in memory formation, consolidation, and reconsolidation. Annu. Rev. Psychol., 61, 49–79.