Long-Term Potentiation: Importance & 17 Ways to Increase It

Modeling Maintenance of Long-Term Potentiation in Clustered Synapses: Long-Term Memory without Bistability

Long-Term Potentiation: Importance & 17 Ways to Increase It

Memories are stored, at least partly, as patterns of strong synapses. Given molecular turnover, how can synapses maintain strong for the years that memories can persist? Some models postulate that biochemical bistability maintains strong synapses.

However, bistability should give a bimodal distribution of synaptic strength or weight, whereas current data show unimodal distributions for weights and for a correlated variable, dendritic spine volume. Thus it is important for models to simulate both unimodal distributions and long-term memory persistence.

Here a model is developed that connects ongoing, competing processes of synaptic growth and weakening to stochastic processes of receptor insertion and removal in dendritic spines. The model simulates long-term (>1 yr) persistence of groups of strong synapses. A unimodal weight distribution results.

For stability of this distribution it proved essential to incorporate resource competition between synapses organized into small clusters. With competition, these clusters are stable for years.

These simulations concur with recent data to support the “clustered plasticity hypothesis” which suggests clusters, rather than single synaptic contacts, may be a fundamental unit for storage of long-term memory. The model makes empirical predictions and may provide a framework to investigate mechanisms maintaining the balance between synaptic plasticity and stability of memory.

1. Introduction

A central question in neuroscience is the mechanism by which memories can be preserved for years.

Long-term memories are at least in part encoded as specific patterns, or “engrams,” of strengthened synapses [1, 2], and long-term synaptic potentiation (LTP) persists for months in vivo [3].

How can specific groups of synapses remain strong for months or years despite turnover of macromolecules and fluctuations in the size and shape of synaptic structures?

Numerous mathematical models have been developed that describe maintenance of long-term memory (LTM) as dependent on bistability of synaptic weights, mediated by positive feedback loops of biochemical reactions, typically thought of as operative in dendritic spines.

Proposed feedback mechanisms have relied on self-sustaining autophosphorylation of CaM kinase II [4, 5], persistent phosphorylation of AMPA receptors by protein kinase A [6], enhanced translation of protein kinase M [7], or self-sustaining clustering of a translation activator, cytoplasmic polyadenylation element binding protein [8]. With these models, LTP switches a synapse from a state of low basal weight to a high weight state and turns on the positive feedback loop. The loop then operates autonomously to keep the synapse in the high weight state indefinitely. However, despite extensive investigation, empirical evidence of a bistable distribution of two distinct synaptic weight states has not, in fact, been obtained. Although some studies [9, 10] have suggested two distinct strength states for synapses, as measured by the amplitude of excitatory postsynaptic currents before and after a stimulus protocol, these studies have only examined the early phase of LTP (

Source: https://www.hindawi.com/journals/np/2015/185410/

Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice

Long-Term Potentiation: Importance & 17 Ways to Increase It

PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings. First, PKMζ is unimportant for LTP or memory.

Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and PKMζ-null mice recruit compensatory mechanisms. We find that whereas PKMζ persistently increases in LTP maintenance in wild-type mice, PKCι/λ, a gene-product closely related to PKMζ, persistently increases in LTP maintenance in PKMζ-null mice.

Using a pharmacogenetic approach, we find PKMζ-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMζ-null mice without the target mRNA. Conversely, a PKCι/λ-antagonist disrupts late-LTP and spatial memory in PKMζ-null mice but not in wild-type mice.

Thus, whereas PKMζ is essential for wild-type LTP and long-term memory, persistent PKCι/λ activation compensates for PKMζ loss in PKMζ-null mice.


How are long-term memories stored in the brain? The formation of memories is believed to depend on the strengthening of connections between neurons.

During learning, neurons produce an enzyme called PKMzeta (or PKMζ), which is thought to be responsible for maintaining the newly strengthened connections. Inhibitors of PKMzeta, such as a drug called ZIP, disrupt long-term memories.

This suggests that the brain may be a computer hard disc in that its stored information — its memories — could be erased.

However, recent experiments on genetically engineered mice have thrown the role of PKMzeta into question. Knockout mice that lack the gene for PKMzeta can still strengthen connections between neurons and can still learn and remember.

Moreover, ZIP still works to reverse the strengthening and to erase long-term memories. This indicates that ZIP can act on something other than the PKMzeta enzyme.

These results have led many neuroscientists to doubt that PKMzeta has anything to do with memory.

Yet there are two possible explanations for the normal memory in PKMzeta knockout mice. First, PKMzeta is not required for memory, so getting rid of it has no effect. Second, PKMzeta is essential for long-term memory in normal mice. However, knockout mice recruit a back-up mechanism for long-term memory storage, which is also sensitive to the effects of ZIP.

To test these possibilities, Tsokas et al. used a modified piece of DNA that prevents neurons with the gene for PKMzeta from producing the enzyme. The DNA blocked memory formation in normal mice, consistent with a role for PKMzeta in memory.

However, it had no effect in knockout mice — the DNA had nothing to work on. This suggests that another molecule does indeed act as a back-up for PKMzeta in these animals.

Further experiments revealed that an enzyme closely related to PKMzeta, called PKCiota/lambda (PKCι/λ), substitutes for PKMzeta during memory storage in the knockout mice.

These findings restore PKMzeta to its early promise. They show that PKMzeta is crucial for long-term memory in normal mice, but that something as important as memory storage has a back-up mechanism should PKMzeta fail. Future work may reveal when and how this back-up becomes engaged.


LTP and long-term memory can be divided into two mechanistically distinct phases—a transient induction and a persistent maintenance (Malinow et al., 1988). Induction is thought to rely solely on post-translational modifications.

Maintenance requires new protein synthesis soon after strong synaptic stimulation or learning, and these newly synthesized proteins are believed to sustain the synaptic potentiation or behavioral modification (Kandel and Schwartz, 1982).

Although numerous signal transduction molecules are important for LTP and long-term memory, most have been implicated in induction, with many participating in either the initial transient potentiation or the mechanisms for upregulating new protein synthesis (Sanes and Lichtman, 1999). In contrast, few molecules have been implicated in maintenance.

Such a maintenance molecule would be both: 1) a product of de novo protein synthesis sufficient to enhance synaptic transmission and 2) a necessary component of the mechanism sustaining synaptic potentiation and long-term memory, as shown by inhibition of the molecule reversing sustained synaptic potentiation and erasing long-term memory.

One hypothesis for a molecular mechanism of maintenance involves the persistent increase in an autonomously active PKC isoform, PKMζ (Sacktor, 2011). LTP and long-term memory maintenance may depend upon the function of PKMζ because data suggest the kinase possesses the two essential properties of a maintenance molecule.

First, PKMζ is produced in LTP by new protein synthesis and is sufficient to potentiate synaptic transmission. PKMζ is generated from a PKMζ mRNA, but this mRNA is translationally repressed in the basal state of neurons (Hernandez et al., 2003).

During LTP, strong afferent synaptic stimulation derepresses the mRNA and rapidly increases the de novo synthesis of PKMζ (Hernandez et al., 2003). The newly synthesized kinase, un most other protein kinases, is autonomously active without the requirement for second messenger stimulation (Sacktor et al.

, 1993; Hernandez et al., 2003), and the autonomous activity of PKMζ is sufficient to enhance synaptic transmission (Ling et al., 2002; 2006; Yao et al., 2008).

Second, multiple inhibitors of PKMζ and a dominant-negative mutated form of PKMζ reverse established LTP maintenance or disrupt long-term memory storage (Ling et al., 2002; Serrano et al., 2005; Pastalkova et al., 2006; Shema et al., 2011; Cai et al., 2011).

Recently, this proposed function of PKMζ has been challenged by new findings that LTP and long-term memory appear normal in PKMζ-null mice (Lee et al., 2013; Volk et al., 2013).

Moreover, the PKMζ-inhibitor ZIP, which disrupts the maintenance of LTP and long-term memory in wild-type animals, disrupts these same processes in PKMζ-null mice (Lee et al., 2013; Volk et al., 2013). Two hypotheses can account for these findings (Frankland and Josselyn, 2013; Matt and Hell, 2013).

First, in a straightforward hypothesis, PKMζ is unnecessary for LTP or long-term memory, and therefore genetically deleting PKMζ has no effect on these processes (Lee et al., 2013; Volk et al., 2013).

Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and compensatory mechanisms emerge in the mutant mice to substitute for PKMζ, which are also inhibited by ZIP. Here, we used a pharmacogenetic approach to distinguish between the 'PKMζ is unnecessary hypothesis' and the 'PKMζ is compensated hypothesis'.

We first confirmed the previously published findings that late-LTP appears similar in PKMζ-null and wild-type mice, and that ZIP (5 µM) applied to the bath 3 hr after tetanization reverses late-LTP in both wild-type mice (Serrano et al., 2005) and PKMζ-null mice (Volk et al., 2013, Figure 1A,B).

In interface chambers in which maximal drug concentrations are achieved slowly, the reversal of late-LTP may be more rapid in wild-type mice than in PKMζ-null mice (time to 50% of the pre-ZIP response is different: wild-type, 129 ± 28 min; PKMζ-null, 311 ± 72 min; t7 = 2.57, p = 0.037, d = 1.64).

Bath applications of ZIP (5 µM) reverse (A) wild-type-LTP maintenance and (B) PKMζ-null-LTP maintenance (filled circles). Above insets, numbered representative fEPSP traces correspond to time points noted below. Below, mean ± SEM. For (A), wild-type, n = 5, average response 5 min before ZIP compared to 3.5 hr post-ZIP, t4 = 4.

83, p = 0.0084, d = 1.85; for (B), PKMζ-null, n = 4, t3 = 3.34, p = 0.045, d = 2.88. Non-tetanized pathways are stable in the presence of ZIP (open circles). For (A), wild-type non-tetanized pathway: 5 min pre-ZIP vs. 3.5 hr post-ZIP; n = 5, t4 = 1.73, p = 0.16; d = 0.49; for (B), PKMζ-null non-tetanized pathway: n = 4, t3 = 0.

82, p = 0.47, d = 0.058. (C) ZIP inhibits both PKMζ and, at higher doses, the autonomous activity of PKCι/λ. The main effects and interactions are all significant (kinase: F1,30 = 85.4, p = 2.77 X 10–10, η2 = 0.036; ZIP concentration: F4,30 = 200.56, p = 3.48 X 10–21, η2 = 0.34; interaction: F4,30 = 26.59, p = 1.98 X 10–9, η2 = 0.045).

Post-hoc tests show the kinases respond differently at 1 µM and 2 µM ZIP. (D, E), ZIP blocks EPSC potentiation produced by postsynaptic dialysis of PKMζ or PKCι/λ in CA1 pyramidal cells in hippocampal slices. ZIP (5 µM) is applied to the bath prior to obtaining whole-cell patch.

Above insets, numbered representative EPSC traces correspond to time points noted below. Statistical comparisons are at 15 min after whole-cell patch. (D) PKMζ: n’s = 4, F2,11 = 18.07, p = 0.0007, d = 1.78; post-hoc tests: PKMζ vs. baseline, p = 0.0012; PKMζ vs. PKMζ + ZIP, p = 0.0018; PKMζ + ZIP vs. baseline, p = 0.94.

(E) PKCι/λ: n’s = 4, F2,11 = 35.2, p = 1.66 X 10–5, d = 1.79; post-hoc tests: PKCι/λ vs. baseline, p

Source: https://elifesciences.org/articles/14846

The reemergence of long-term potentiation in aged Alzheimer’s disease mouse model

Long-Term Potentiation: Importance & 17 Ways to Increase It

  • Inhibition–excitation balance
  • Long-term potentiation

Mouse models of Alzheimer’s disease (AD) have been developed to study the pathophysiology of amyloid β protein (Aβ) toxicity, which is thought to cause severe clinical symptoms such as memory impairment in AD patients.

However, inconsistencies exist between studies using these animal models, specifically in terms of the effects on synaptic plasticity, a major cellular model of learning and memory. Whereas some studies find impairments in plasticity in these models, others do not.

We show that long-term potentiation (LTP), in the CA1 region of hippocampal slices from this mouse, is impared at Tg2576 adult 6–7 months old. However, LTP is inducible again in slices taken from Tg2576 aged 14–19 months old.

In the aged Tg2576, we found that the percentage of parvalbumin (PV)-expressing interneurons in hippocampal CA1-3 region is significantly decreased, and LTP inhibition or reversal mediated by NRG1/ErbB signaling, which requires ErbB4 receptors in PV interneurons, is impaired.

Inhibition of ErbB receptor kinase in adult Tg2576 restores LTP but impairs depotentiation as shown in aged Tg2576. Our study suggests that hippocampal LTP reemerges in aged Tg2576. However, this reemerged LTP is an insuppressible form due to impaired NRG1/ErbB signaling, possibly through the loss of PV interneurons.

Progressive loss of memory function and the accumulation of amyloid β protein (Aβ) in the brain are key characteristics of Alzheimer’s disease (AD) pathology1,2.

Previous findings have demonstrated that synaptic plasticity, regarded as the cellular basis for learning and memory3, is vulnerable to exposure to high levels of Aβ; hippocampal long-term potentiation (LTP) is impaired following exogenous exposure to soluble oligomeric Aβ4,5,6.

To try to understand how memory function in AD becomes dysregulated, a vast number of studies have looked to determine the mechanisms underlying the Aβ-mediated impairment of synaptic plasticity.

To closely model AD pathology, transgenic mice carrying mutant amyloid precursor protein (APP), which causes excessive production of Aβ in the brain, have been developed, and are used to investigate the pathophysiology of Aβ toxicity7.

However, inconsistencies remain in the pathological readouts from such animals; whether LTP is inhibited or normal in these mouse models remains unclear, as notably reported in papers using one of the most frequently used transgenic mice harboring the Swedish mutation in APP (APP695SWE)8,9.

Here, whilst some studies report inhibition of LTP in the APP transgenic mouse10,11,12, others find no inhibition of LTP between 3 months and 12 months of age in these AD model mice13,14,15,16. An important aspect to consider in relation to this is the diverse ages of the animals used in these studies (ranging from 3 to 18 months of age).

Here, some studies have reported a relationship between abnormal synaptic plasticity and the age of the APP transgenic mouse used, with young animals displaying profound LTP impairments that are not present in the older animals15,17. The reason for this apparent age-dependent effect, however, is unknown.

One explanation for these age-dependent effects could relate to the interneuronal control of pyramidal neurons.

Most GABAergic interneurons in the hippocampal CA1 region innervate their synapses onto pyramidal cell dendrites where neuronal computation, such as modulation, integration of synaptic inputs and expression of synaptic plasticity, mainly occurs18,19,20.

Recently, it was shown that loss of GABAergic interneurons leads to an enhanced LTP in the hippocampal CA1 region21. Interestingly, a significant decrease in the number of GABAergic interneurons was observed in the hippocampus of the AD mouse model and indeed in AD patients22,23.

Furthermore, enhanced LTP was accompanied with reduced numbers of interneurons in the dentate gyrus of the mouse model of both amyloidosis and tauopathy24. One possible explanation, therefore, is that the age-dependent loss of GABAergic interneurons in the transgenic mice actually serves to facilitate the induction of LTP in the hippocampal CA1 region.

Both ErbB receptor kinases in GABAergic interneurons and the endogenous ligand neuregulin 1 (NRG1), a neurotropic factor implicated in neural development, neurotransmission and synaptic plasticity25, have been variously shown to regulate hippocampal LTP: (1) neutralization of endogenous NRG1 in the hippocampus enhances the magnitude of hippocampal LTP at CA1 region26, whereas addition of exogenous NRG1 suppresses the induction of LTP27,28; (2) inhibition of ErbB4 kinase increases the magnitude of hippocampal LTP, an effect similarly observed in ErbB4 knockout mice29,30; (3) ErbB4 is selectively expressed in interneurons but not in pyramidal neurons31, and ErbB4 deletion in parvalbumin (PV) interneurons, the major type of GABAergic interneurons in hippocampus32,33, completely blocks the LTP regulation induced by NRG126,30. Critically, NRG1 and ErbB4 distribution was found to be altered in the brains spotted with neuritic plaques in the mouse model of AD and in AD patients34. We therefore hypothesized that the age-dependent dysregulation of hippocampal LTP in the APP transgenic mouse was underpinned by the Aβ-mediated impairment of NRG1/ErbB signaling, leading to the facilitation of LTP. Here we demonstrate a possible link between a loss of interneurons, NRG1/ErbB signaling dysregulation and changes in synaptic plasticity in a mouse model of AD.

To examine whether LTP in Tg2576 mice is altered in an age-dependent manner, we compared LTP in two different age groups, 6–7 months old (adult) and 14–19 months old (aged), in the hippocampal CA1 region.

Tg2576 is a well-documented mouse model of AD showing high levels of Aβ and memory impairment8,10, and soluble Aβ in the brains of these transgenic animals begins to be significantly accumulated at around 6 months of age after a non-accumulation phase from birth11,35.

Increased fEPSP induced by high frequency stimulation (HFS) at the Schaffer collateral pathway was maintained for 2 hours in adult littermate WT, but returned to baseline levels in adult Tg2576 (Tg: 113.2 ± 7.4% of baseline, n = 8, closed circle; WT: 159.1 ± 9.4%, n = 8, open circle, P  0.

05, Fig. 1B). Interestingly, the observed time period for LTP inhibition and reappearance in Tg2576 mice is very similar to a previous report which pointed out that soluble Aβ levels in the brain was not correlated with the LTP deficit in aged animals15.

Clearly, then, there is an interesting disparity in impaired synaptic plasticity in these AD mouse models; whilst LTP is inhibited at early ages after soluble Aβ accumulation begins, it reemerges at older ages.

Figure 1: The reemergence of LTP in the hippocampus of aged Tg2576.

(A) Applying two trains of tetanus stimuli (10 Hz in s, 3 s inter-train interval) to the Schaffer collateral pathway evoked LTP in the hippocampal CA1 region in 6–7 months old WT (open circle, n = 8) but did not in Tg2576, where the fEPSP was gradually decreased to the baseline level 2 hours after LTP induction by HFS (closed circle, n = 8). (B) In 14–19 months old animals, LTP was observed in both WT (open circle, n = 7) and Tg2576 (closed circle, n = 7) mice, and their increased fEPSP levels were not significantly different (P > 0.05). Error bars represent standard error of the mean (SEM). fEPSP = field excitatory postsynaptic potential.

Decreased percentage of PV interneurons in hippocampal CA region of aged Tg2576

One possible explanation for the LTP reemergence in aged Tg2576 would be the decreased density of inhibitory interneurons in hippocampus, which could conceivably contribute to an enhancement of excitatory signaling and the facilitation of LTP.

To test this hypothesis, we specifically measured the percentage of PV interneurons in hippocampal CA1-3 region. PV interneurons constitute a major proportion of GABAergic interneurons in the hippocampus32,33. Further, PV interneurons are critical for the NRG1/ErbB4-mediated down-regulation of LTP expression at the Schaffer collateral-CA1 synapse26,30.

PV-immunoreactive (IR) neurons were observed in hippocampus of both the adult and aged Tg2576 (Fig. 2A,B). To calculate the percentage of PV interneurons, NeuN and PV-IR neurons were counted in whole CA subfields, and the ratio of PV-IR to NeuN-IR cells was estimated.

We found that the proportion of PV interneurons to NeuN-positive cells was significantly decreased in aged Tg2576 compared with adult Tg2576 (Fig. 2C). Importantly, this reduction was not solely due to the aging effect, since there was no significant difference in the percentage of the neurons between adult and aged littermate WT.

Interestingly, it was recently shown that loss of PV interneurons is associated with enhanced LTP in a mouse model of multiple sclerosis36, suggesting a strong possibility of this neuronal loss enhancing LTP in aged Tg2576.

Figure 2: The percentage of parvalbumin (PV) interneurons is reduced in aged Tg2576.

(A) Representative PV immunohistochemistry stains in the hippocampus of a 6–7 months old (adult) WT (n = 4) and Tg2576 (n = 4) mouse.

PV-positive interneurons are shown in the hippocampus at a low magnification (original magnification, ×40), and at a closer distance from the CA1 (original magnification, ×100, pointed by arrowheads) and CA3 (original magnification, ×100).

(B) Representative PV immunohistochemistry stains in the hippocampus of a 14–19 months old (aged) WT (n = 6) and Tg2576 (n = 6) mouse. (C) The ratio of PV-positive cells to NeuN-positive cells (data not shown) in aged Tg2576 is significantly lower than in adult Tg2576 (**P  0.05, Fig. 3F).

Inhibition of ErbB receptor kinase in adult Tg2576 can mimic the changes of the synaptic plasticity in aged Tg2576

If the impaired NRG1/ErbB signaling is actually correlated with the reemerged LTP in aged Tg2576 mice, disrupting NRG1/ErbB signaling in adult Tg2576 might induce similar synaptic characteristics to those observed in aged Tg2576: normal LTP but impaired depotentiation.

We therefore investigated the effect of blocking the ErbB4 receptor on synaptic plasticity in adult Tg2576.

To do this, we first perfused hippocampal slices from adult Tg2576 with 10 μM PD158780, an inhibitor of ErbB receptor kinase, for 10 minutes starting 2 minutes before HFS application.

LTP was induced in PD158780 treated slices, and the potentiated fEPSP was maintained for more than 2 hours (Tg vehicle: 108.8 ± 8.8%, n = 6, grey closed circle; WT vehicle: 146.4 ± 6.7%, n = 3, grey open circle; Tg PD158780: 154.6 ± 3.9%, n = 6, maroon closed circle, P

Source: https://www.nature.com/articles/srep29152

Effects of Chronic and Acute Lithium Treatment on the Long-term Potentiation and Spatial Memory in Adult Rats

Long-Term Potentiation: Importance & 17 Ways to Increase It

  1. Squire, LR, Wixted, JT, Clark, RE (2007). Recognition memory and the medial temporal lobe: a new perspective. Nat Rev Neurosci. 8, 872-883.

  2. Andersen, P, Moser, E, Moser, MB, Trommald, M (1996). Cellular correlates to spatial learning in the rat hippocampus. J Physiol Paris. 90, 349.

  3. Neves, G, Cooke, SF, Bliss, TV (2008). Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nat Rev Neurosci. 9, 65-75.

  4. Yu, IT, Kim, JS, Lee, SH, Lee, YS, Son, H (2003). Chronic lithium enhances hippocampal long-term potentiation, but not neurogenesis, in the aged rat dentate gyrus. Biochem Biophys Res Commun. 303, 1193-1198.

  5. Zhu, ZF, Wang, QG, Han, BJ, William, CP (2010). Neuroprotective effect and cognitive outcome of chronic lithium on traumatic brain injury in mice. Brain Res Bull. 83, 272-277.

  6. Zarrindast, MR, Fazli-Tabaei, S, Ahmadi, S, Yahyavi, SH (2006). Effect of lithium on morphine state-dependent memory of passive avoidance in mice. Physiol Behav. 87, 409-415.

  7. Hashimoto, R, Hough, C, Nakazawa, T, Yamamoto, T, Chuang, DM (2002). Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation. J Neurochem. 80, 589-597.

  8. Zhang, X, Heng, X, Li, T, Li, L, Yang, D, Zhang, X (2011). Long-term treatment with lithium alleviates memory deficits and reduces amyloid-β production in an aged Alzheimer’s disease transgenic mouse model. J Alzheimers Dis. 24, 739-749.

  9. Pachet, AK, Wisniewski, AM (2003). The effects of lithium on cognition: an updated review. Psychopharmacology (Berl). 170, 225-234.

  10. Honig, A, Arts, BM, Ponds, RW, Riedel, WJ (1999). Lithium induced cognitive side-effects in bipolar disorder: a qualitative analysis and implications for daily practice. Int Clin Psychopharmacol. 14, 167-171.

  11. Kocsis, JH, Shaw, ED, Stokes, PE, Wilner, P, Elliot, AS, Sikes, C (1993). Neuropsychologic effects of lithium discontinuation. J Clin Psychopharmacol. 13, 268-275.

  12. Stip, E, Dufresne, J, Lussier, I, Yatham, L (2000). A double-blind, placebo-controlled study of the effects of lithium on cognition in healthy subjects: mild and selective effects on learning. J Affect Disord. 60, 147-157.

  13. Vestergaard, P, Poulstrup, I, Schou, M (1988). Prospective studies on a lithium cohort. 3. Tremor, weight gain, diarrhea, psychological complaints. Acta Psychiatr Scand. 78, 434-441.

  14. Son, H, Yu, IT, Hwang, SJ, Kim, JS, Lee, SH, Lee, YS (2003). Lithium enhances long-term potentiation independently of hippocampal neurogenesis in the rat dentate gyrus. J Neurochem. 85, 872-881.

  15. Shim, SS, Hammonds, MD, Ganocy, SJ, Calabrese, JR (2007). Effects of subchronic lithium treatment on synaptic plasticity in the dentate gyrus of rat hippocampal slices. Prog Neuropsychopharmacol Biol Psychiatry. 31, 343-347.

  16. Amdisen, A (1978). Clinical and serum-level monitoring in lithium therapy and lithium intoxication. J Anal Toxicol. 2, 193-202.

  17. Bitiktaş, S, Tan, B, Kavraal, Ş, Yousef, M, Bayar, Y, Dursun, N (2017). The effects of intra-hippocampal L-thyroxine infusion on long-term potentiation and long-term depression: a possible role for the αvβ3 integrin receptor. J Neurosci Res. 95, 1621-1632.

  18. Artis, AS, Bitiktas, S, Taşkın, E, Dolu, N, Liman, N, Suer, C (2012). Experimental hypothyroidism delays field excitatory post-synaptic potentials and disrupts hippocampal long-term potentiation in the dentate gyrus of hippocampal formation and Y-maze performance in adult rats. J Neuroendocrinol. 24, 422-433.

  19. Suer, C, Dolu, N, Artis, AS, Sahin, L, Aydogan, S (2011). Electrophysiological evidence of biphasic action of carnosine on long-term potentiation in urethane-anesthetized rats. Neuropeptides. 45, 77-81.

  20. Nikitin, ES, Balaban, PM (2014). Compartmentalization of non-synaptic plasticity in neurons at the subcellular level. Neurosci Behav Physiol. 44, 725-730.

  21. Chavez-Noriega, LE, Halliwell, JV, Bliss, TV (1990). A decrease in firing threshold observed after induction of the EPSP-spike (E-S) component of long-term potentiation in rat hippocampal slices. Exp Brain Res. 79, 633-641.

  22. Zhang, W, Linden, DJ (2003). The other side of the engram: experience-driven changes in neuronal intrinsic excitability. Nat Rev Neurosci. 4, 885-900.

  23. Antonelli, T, Ferioli, V, Lo Gallo, G, Tomasini, MC, Fernandez, M, O’Connor, WT (2000). Differential effects of acute and short-term lithium administration on dialysate glutamate and GABA levels in the frontal cortex of the conscious rat. Synapse. 38, 355-362.

  24. Chavez-Noriega, LE, Bliss, TV, Halliwell, JV (1989). The EPSP-spike (ES) component of long-term potentiation in the rat hippo-campal slice is modulated by GABAergic but not cholinergic mechanisms. Neurosci Lett. 104, 58-64.

  25. Hernández, F, Borrell, J, Guaza, C, Avila, J, Lucas, JJ (2002). Spatial learning deficit in transgenic mice that conditionally over-express GSK-3beta in the brain but do not form tau filaments. J Neurochem. 83, 1529-1533.

  26. Klein, PS, Melton, DA (1996). A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci U S A. 93, 8455-8459.

  27. Moon, RT, Kohn, AD, De Ferrari, GV, Kaykas, A (2004). WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet. 5, 691-701.

  28. Peineau, S, Taghibiglou, C, Bradley, C, Wong, TP, Liu, L, Lu, J (2007). LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron. 53, 703-717.

  29. Hooper, C, Markevich, V, Plattner, F, Killick, R, Schofield, E, Engel, T (2007). Glycogen synthase kinase-3 inhibition is integral to long-term potentiation. Eur J Neurosci. 25, 81-86.

  30. Zhu, LQ, Wang, SH, Liu, D, Yin, YY, Tian, Q, Wang, XC (2007). Activation of glycogen synthase kinase-3 inhibits long-term potentiation with synapse-associated impairments. J Neurosci. 27, 12211-12220.

  31. Harwood, AJ, Agam, G (2003). Search for a common mechanism of mood stabilizers. Biochem Pharmacol. 66, 179-189.

  32. Shim, SS (2012). Lithium enhances synaptic plasticity: implication for treatment of bipolar disorder. Bipolar disorder – a portrait of a complex mood disorder, Barnhill, J, ed. London: InTech, pp. 41-54

  33. Nonaka, S, Hough, CJ, Chuang, DM (1998). Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx. Proc Natl Acad Sci U S A. 95, 2642-2647.

  34. Rowe, MK, Chuang, DM (2004). Lithium neuroprotection: molecular mechanisms and clinical implications. Expert Rev Mol Med. 6, 1-18.

  35. Seelan, RS, Khalyfa, A, Lakshmanan, J, Casanova, MF, Parthasarathy, RN (2008). Deciphering the lithium transcriptome: microarray profiling of lithium-modulated gene expression in human neuronal cells. Neuroscience. 151, 1184-1197.

  36. Lenox, RH, McNamara, RK, Watterson, JM, Watson, DG (1996). Myristoylated alanine-rich C kinase substrate (MARCKS): a molecular target for the therapeutic action of mood stabilizers in the brain?. J Clin Psychiatry. 57, 23-31.

  37. Morris, RG, Garrud, P, Rawlins, JN, O’Keefe, J (1982). Place navigation impaired in rats with hippocampal lesions. Nature. 297, 681-683.

  38. Jeltsch, H, Bertrand, F, Lazarus, C, Cassel, JC (2001). Cognitive performances and locomotor activity following dentate granule cell damage in rats: role of lesion extent and type of memory tested. Neurobiol Learn Mem. 76, 81-105.

  39. Bliss, TV, Collingridge, GL (1993). A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 361, 31-39.

  40. Ghorbanalizadeh-Khalifeh-Mahaleh, B, Taheri, S, Sahebgharani, M, Rezayof, A, Haeri-Rohani, A, Zarrindast, MR (2008). Intra-dorsal hippocampal microinjections of lithium and scopolamine induce a cross state-dependent learning in mice. Arch Iran Med. 11, 629-638.

  41. Bora, E, Vahip, S, Akdeniz, F, Gonul, AS, Eryavuz, A, Ogut, M (2007). The effect of previous psychotic mood episodes on cognitive impairment in euthymic bipolar patients. Bipolar Disord. 9, 468-477.

  42. López-Jaramillo, C, Lopera-Vásquez, J, Ospina-Duque, J, García, J, Gallo, A, Cortez, V (2010). Lithium treatment effects on the neuropsychological functioning of patients with bipolar I disorder. J Clin Psychiatry. 71, 1055-1060.

  43. Tsaltas, E, Kontis, D, Boulougouris, V, Papakosta, VM, Giannou, H, Poulopoulou, C (2007). Enhancing effects of chronic lithium on memory in the rat. Behav Brain Res. 177, 51-60.

  44. Yan, XB, Hou, HL, Wu, LM, Liu, J, Zhou, JN (2007). Lithium regulates hippocampal neurogenesis by ERK pathway and facilitates recovery of spatial learning and memory in rats after transient global cerebral ischemia. Neuropharmacology. 53, 487-495.

  45. Yazlovitskaya, EM, Edwards, E, Thotala, D, Fu, A, Osusky, KL, Whetsell, WO (2006). Lithium treatment prevents neurocognitive deficit resulting from cranial irradiation. Cancer Res. 66, 11179-11186.

  46. Sharifzadeh, M, Aghsami, M, Gholizadeh, S, Tabrizian, K, Soodi, M, Khalaj, S (2007). Protective effects of chronic lithium treatment against spatial memory retention deficits induced by the protein kinase AII inhibitor H-89 in rats. Pharmacology. 80, 158-165.

  47. Nocjar, C, Hammonds, MD, Shim, SS (2007). Chronic lithium treatment magnifies learning in rats. Neuroscience. 150, 774-788.

  48. Youngs, RM, Chu, MS, Meloni, EG, Naydenov, A, Carlezon, WA, Konradi, C (2006). Lithium administration to preadolescent rats causes long-lasting increases in anxiety- behavior and has molecular consequences. J Neurosci. 26, 6031-6039.

Source: http://www.cpn.or.kr/journal/view.html?doi=10.9758/cpn.2019.17.2.233

What Is Long-Term Potentiation (LTP), And Why Is It Important?

Long-Term Potentiation: Importance & 17 Ways to Increase It

Long-term potentiation, or LTP, is one of the main mechanisms involved in synaptic plasticity. It occurs when the connections between neurons (synapses) are “strengthened,” which changes the way they interact with each other while processing information.

Such changes to the brain’s connectivity are some of the primary ways our brains learn and store new information.

Read on to learn more about this process, why it’s so important to cognitive functioning, and what kinds of lifestyle and health factors can impair the brain’s ability to carry out this important function!

Long-Term Potentiation: A Basic Overview

The human brain is comprised of 100 billion neurons, each of which connects to up to 10,000 other brain cells through small “gaps” or “junctions” called synapses.

Our brains incorporate and store new information – such as skills or memories – by adjusting both where and how different individual neurons connect and “talk” to each other. This ability to change and adapt how neurons connect to each other – and thus alter how they process and store information – is referred to as synaptic plasticity.

“Synaptic plasticity” is a general process that can take many forms. For example, it may refer to the “strengthening” or “weakening” of individual neuronal connections at existing synapses. Alternatively, it can also refer to the creation of entirely new connections between formerly-unconnected brain cells (a process called synaptogenesis).

Long-term potentiation – or just “LTP” for short – is one of the most important processes involved in synaptic plasticity at existing neural synapses.

Specifically, it means that the existing connection between two brain cells is strengthened, thereby making it easier for these two neurons to stimulate each other when the other is activated.

This is one of the main mechanisms involved in how we store long-term memories or learn new information and skills [1, 2].

LTP occurs when two different neurons are stimulated – a role that is often (though not always) carried out by the neurotransmitter glutamate. Glutamate is the main “excitatory” neurotransmitter in the brain, and contributes significantly to the formation of memories and learning [3].

When two neurons repeatedly “fire” together, they become sensitized, and more responsive to stimulation by each other.

It’s almost as if the neurons “remember” that they were previously stimulated, and they become easier to activate. This increase in excitability can last anywhere from hours to days.

The synapse is therefore said to be stronger because it can carry impulses easier [1, 2].

LTP was originally discovered in the hippocampus, a part of the brain that is believed to be heavily involved in learning and memory, spatial navigation, and emotion. Neurons from the hippocampus connect with neurons of the amygdala, one of the main brain areas responsible for processing emotions. This may be why certain memories make you feel happy or sad [4, 5].

However, LTP has also been observed throughout many other regions of the brain, including the cerebellum, cerebral cortex, amygdala, and hippocampus [2].

Long-Term Potentiation Requires Maintenance

LTP typically occurs in three main steps [1]:

  1. The “induction” phase
  2. The “expression” phase
  3. The “maintenance” phase

The first two steps – “induction” and “expression” – are the initial stages of LTP. They correlate to short-term memories. They happen when you learn something new, perhaps during a lecture. This is the beginning of long-term potentiation.

However, without the third step – “maintenance” – you probably wouldn’t be able to recall this information later on.

When you “rehearse” new memories or information – such as by sitting at home and studying new information – over time these new neural pathways are re-activated again, and the memories become more stable (“consolidated”).

This occurs because of increases in proteins that will actually change the shape of neurons to accommodate the information.

This is the process of maintenance – and it allows us to store information for years at a time within a single neuronal pathway [6].

How LTP Works

NMDA-receptor dependent LTP is the most well-researched form of long-term potentiation. This is how it works [7]:

LTP occurs in two main phases, which could be thought of as the “learning” process and then the “memory-consolidation” process.

Early-Phase LTP (“learning”):

  • Glutamate binds to NMDA receptors and excites the neuron. This dislodges magnesium (Mg2+) ions that block the channel. Removal of the Mg2+ allows for calcium to enter the cell.
  • Calcium ions flow into the cell and activate protein kinase C (PKC) and calmodulin/calcium-dependent protein kinase II (CaMKII).
  • PKC and CaMKII activity increases the number of receptors at the surface of the neuron (the cellular membrane). The more receptors that are present at the surface, the more readily that neuron can be activated by other neighboring cells that connect with it.
  • AMPA receptors are then increased and activated to improve conductivity. This allows more positive ions (such as calcium and sodium) to enter the cell. As the cell becomes more positively charged, the more easily it is “activated.”

Late-Phase LTP (“consolidation”):

  • All of the activity of early phase long-term potentiation continues; but now more proteins are being created. These include more receptors to mediate LTP, structural proteins, and proteins that promote cell survival and health.
  • CaMKII and PKC activate extracellular signal-regulated kinases (ERKs).
  • ERKs increase protein production, which further changes the cellular structure of the neuron.
  • Another important protein, cAMP response element-binding protein (CREB), activates a variety of genes that assist in maintaining the new shape of the synapse.
  • All of the above result in changes to the overall structure and connectivity at the synapse.

Long-Term Depression (LTD)

As opposed to long-term potentiation, the efficiency of information transfer between neurons can actually be decreased at specific synapses by a process called long-term depression, or “LTD” for short.

Basically, long-term depression is the “opposite” of long-term potentiation, in that it weakens the connection strength of individual synapses [8].

However, even though it is in some ways the “opposite” of LTP, LTD also has many of the same characteristics, in that it involves making long-lasting structural and functional changes to a synapse over the course of hours or days [8].

Under typical conditions, LTD is a normal part of synaptic plasticity that aids in the storage of information. You could think of it as our way of letting certain memories “decay” so that we can prioritize the storage of other, more important, information. For example, LTD is a fundamental part of the way we learn new motor skills [8, 1].

However, some research suggests that LTD may be abnormally increased in some neurological conditions, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis (MS), and even diabetes. LTD is also suspected to play a role in the development of drug addiction and some other psychiatric conditions [9, 10].

Similarly, we see increased levels of LTD in the brain during periods of acute stress, which may explain why people sometimes can’t recall information well when panicking [9].

Factors That May Impair Long-Term Potentiation

Because LTP is fundamental for so many different brain processes, disruptions to it can potentially contribute to a wide variety of different symptoms and health conditions.

1) Drugs of Abuse

Many different drugs of abuse – including opiates, amphetamines, and cocaine – are believed to cause long-lasting changes in the strength of synapses.

These changes may play a key role in some of the central “symptoms” of drug abuse, such as the development of “fond memories” of previous drug abuse that can cause an individual to continue to compulsively seek out the drug in the future.

By extension, these behaviors and habits can be strengthened and reinforced over time (via LTP) to result in full-blown drug addiction [11].

2) Neurodegenerative Diseases

Alzheimer’s and Parkinson’s disease are each marked by structural changes to the brain and its neurons that ultimately impair LTP, which can eventually lead to significant impairments in a persons’ ability to store memories and function properly in daily life [12, 13].

3) Anxiety and Stress

According to some preliminary research, chronic stress may lead to increased LTP – particularly in certain brain regions, such as the amygdala. However, this increase can actually be harmful, because it causes structural changes in the neurons that reinforce our susceptibility and sensitivity to fear. These long-term changes may contribute to persistent anxiety disorders [14, 15].

4) Depression

According to some preliminary research, patients with depression show evidence of abnormalities in the process of LTP, which may contribute to some of the adverse structural changes in the brain often seen in depression patients. For example, excessive LTP could lead to the creation of persistent negative memories, which could contribute to the formation of chronic patterns of negative mood [16].

5) Schizophrenia

Patients with schizophrenia often have cognitive deficits. Some researchers have proposed that this may in part be caused by impaired LTP – especially in certain brain regions involved in cognition, such as the hippocampus [17].

6) Sleep Deprivation

Sleep is extremely vital for the brain’s ability to encode and store new information, and transfer it into long-term memory for later use.

Unsurprisingly, not getting more than 6 hours of sleep a night has been reported to cause impairments in the “maintenance” stage of LTP, thereby making it more difficult to store information over time [18].

7) Autism

Some early evidence suggests that patients with autism may have abnormalities in their brains’ ability to initiate LTP, which may contribute to some of the cognitive or other symptoms of autism spectrum disorders [19].

8) Epilepsy

Patients with epilepsy and other disorders involving recurrent seizures often report issues with memory and learning, which some researchers have proposed may be the result of faulty long-term potentiation caused by the excessive neural activity from seizures [20].

9) High-Fat Diets

Eating high amounts of fat has been associated with significant impairments in memory and learning. Some researchers believe that this may be caused by the presence of palmitic acid, a fatty acid that is commonly consumed in excessive amounts by people with high-fat diets [21].

Further Reading

Now that we’ve covered the basics of LTP, why it’s important, and some of the factors that can influence this important brain process, in the next post we’ll explore some of the potential factors that may help stimulate LTP (and other plasticity-related processes) throughout the brain!

>>>16 Strategies That May Stimulate Long-Term Potentiation

Source: https://selfhacked.com/blog/long-term-potentiation-ltp/