Metaplasticity

Main page: Neurophysiology of Learning and Memory

**Introduction** There have been many experiments conducted to test the synaptic plasticity of the brain as it is the primary model for memory formation. However, in the last 15 to 20 years, researchers have discovered that each synapse which causes a synaptic change on the dendritic spine is plastic itself. The discovery led to the theory that synaptic plasticity can be modulated – that is, the plasticity of synaptic plasticity, which W.C. Abraham has coined the term “metaplasticity” (Bear, 1995). It is a higher-order form of synaptic plasticity. Deisseroth et al (1995) mentioned that the impact of the previous stimulation can be altered by metaplasticity following another stimulus. For example, in a synaptic pathway, the original stimulus generates long-term potentiation (LTP). After it undergoes a special treatment, the same stimulus causes long-term depression (LTD) to occur. This modification is mediated by metaplasticity. It can be used to maintain [|homeostasis], ensuring that neither an excited response reaches its saturation point, nor an inhibited response reaches extinction.


 * || **Table of Contents**
 * Research development
 * Discovery of “metaplasticity” and its initial research
 * Experimental Evidence
 * Mechanisms
 * NMDAR-Mediated Metaplasticity
 * mGluR-Mediated Metaplasticity
 * Role of PKMzeta
 * Clinical implications and treatments
 * Neuropsychiatric and Neurodegenerative Disorders
 * Relation to metaplasticity
 * Treatments
 * Cocaine-induced metaplasticity
 * N-acetylcystein functions
 * Possible Treatments ||  ||

**Research Development**

The term “metaplasticity” was first coined by W.C. Abraham and then later published by M.F. Bear in 1995. For the next couple of years, researchers have extensively studied rats’ brains to observe metaplasticity. Mechanisms were suggested simultaneous by different researchers, although many remained theoretical. W.C. Abraham and M.F. Bear gave simple guidelines for when observing metaplasticity: when a prior synaptic activity causes a change in direction of plasticity or the degree of plasticity by a specific pattern of activation, then metaplasticity has occurred (Abraham & Bear, 1997). This term was coined because many researchers reported “paradoxical” results for their studies. Many studies showed that low level of NMDAR activation can inhibit a subsequent LTP, and causes synaptic changes (Huang et al., 1992; O’Dell & Kandel, 1994; Izumi et al, 1992). Researchers believed that this is a homeostatic response. Similar responses found in LTD, where the subsequent LTD is enhanced by prior activity (Abraham & Tate, 1997). However, these results are also evidence for the existence of metaplasticity.

While older studies focused on observing and validating the occurrence of metaplasticity, newer studies generally focus on the cellular and molecular mechanisms of metaplasticity, clinical applications of metaplasticity, and the manipulation of metaplasticity. These studies aim to find ways to alter LTP and LTD, and ultimately find treatments for related diseases. Newer studies have found that researchers are now able to prime synapses to produce a preferred type of plasticity (Lee & Dong, 2011). Ultimately, metaplasticity suggests that the threshold levels for LTP and LTD are constantly adjusted.

**Mechanisms**

In 2012, most if not all researchers can agree that metaplasticity undoubtedly occurs. However, the researchers still cannot unanimously agree on one specific mechanism for metaplasticity.


 * NMDAR-Mediated Metaplasticity**

LTP can be induced by high frequency stimulation, whereas LTD is induced by low-frequency stimulation. However, both kinds of induction require the activation of NMDAR. N-methyl-d-aspartate receptors (NMDARs) are highly important in regulating and controlling synaptic changes occurring in the brain. There are several different ways to induce NMDAR-mediated LTP, either in the dentate gyrus through the co-activation of NMDAR and mGluR (Yang et al, 2003), or in the CA1 region of hippocampus by anoxia (Rufini et al, 2009). Since NMDAR activation mediate many forms of plasticity, researchers thought that perhaps, the changes in NMDAR functions may be related to metaplasticity. NR2A and NR2B are two subunits of NMDARs. The changes in NR2A and NR2B ratio have shown to have an impact on LTD/LTP induction, specifically its threshold. Modification of LTD and LTP threshold is a characteristic of metaplasticity. By elevating the NR2A/NR2B ratio, the threshold for LTD induction is also increased. Conversely, a decrease in NR2A/NR2B ratio leads to a decrease in LTD induction threshold, which favoursLTD induction (Yashiro & Philpot, 2008). The exact molecular and cellular mechanism for this NR2A/NR2B ratio-mediated metaplasticity is still unknown. Some hypothesize that these two subunits of NMDAR are crucial in regulating calcium influx. Other researchers predict that there’s an involvement of CamKII in association with NR2B (Barria & Malinow, 2005).


 * mGluR-Mediated Metaplasticity**

NMDAR-mediated metaplasticity generates an inhibition of subsequent LTP (by increasing its induction threshold). On the contrary, metabotropic glutamate receptors (mGluR) mediated metaplasticity facilitates the induction of subsequent LTP. mGluR is a G-protein-coupled receptor which activates signaling cascade downstream. The increased induction of LTP by mGluR is mediated by a local synthesis of proteins, which converts the decaying LTP into a stable form of LTP (Raymond et al, 2000). Through the activation of mGluR, protein kinase Mζ (PKMζ) is produced. This protein is a plasticity-related protein, and is associated with the increased induction of LTP (Sajikumar & Korte, 2010).

Although there have been some studies on this mechanism, it still has not been widely studied. Many current papers suggest that further studies regarding this mechanism are required before proposing a specific pathway.

**Clinical Implications and Treatments**


 * Neuropsychiatric Disorders**

Many neuropsychiatric disorders have documented dysfunctional pathways in learning and memory. Undoubtedly, there are deficits in the synaptic plasticity in the individuals with neuropsychiatric disorders (Barkus et al., 2009). Neurodegenerative diseases such as Alzheimer’s disease, Huntington’s disease, as well as Parkinson’s disease have all been related to glutamate-mediated dysfunction (Ondrejcak et al., 2010). The importance of glutamate functions is undeniable in relation to these neuropsychistric and neurodegenerative disorders. Stressors associated with these disorders may also have a negative impact on LTP, which may lead to mental dysfunction and memory deficits (Zorumski & Rubin, 2011). Other studies have shown that LTP induction can be impaired by behavioural stress with the activation of NMDAR (Kim & Diamond, 2002). The untimely NMDAR activation may be a possible contributor to the disorders with memory deficits. Therefore, in neurodegenerative and neuropsychiatric conditions, it is possible that changes associated with metaplasticity may occur (Zorumski & Izumi, 2012).

Metaplasticity can be triggered by many different stressors. The process itself is complex, and involves many plasticity-related proteins. However, it is known that this process makes the induction of LTP more difficult, and therefore makes LTD induction easier. The problem with this shift is that it can lead to an imbalanced ratio of inhibitory to excitatory connectivity. Several studies also suggested that this imbalance of synaptic activities may be a contributor to psychotic disorders, such as schizophrenia (Javitt, 2004).

Zorumski and Izumi (2012) have proposed a NMDAR-induced pathway with the activation of neurosteroids and signaling cascade (fig. 2). It not only represents a well-organized pathway, but also includes treatment options to inhibit a certain step of the pathway. By inhibiting any one of these steps, LTP induction can be returned to normal. 


 * Cocaine induced metaplasticity**

Addiction to drugs and dangerous substances is a major concern of the society and a huge part of research studies. Addiction can be described by the inability to stop seeking for drugs, and increase the vulnerability for future relapse. This inability to develop appropriate behaviours to prevent drug seeking leads to the theory that there is a deficit in the brain region which regulates and controls motivated behaviour. Specifically, researchers have stated that the deficit resides in the ability to induce plasticity in the nucleus accumbens (Huang, 2009). Effects of substance addiction and misuse is an important and new area of study in metaplasticity. Addiction to cocaine, in particular, is important in the study of metaplasticity.

media type="youtube" key="qADB1JdkYp0" height="346" width="462" align="center" An Australian researcher uses honeybees as animal models to look at how the brain reacts to cocaine. In particular, he wanted to see how the rewards system of the brain reacts to cocaine addiction.

One study by Lee & Dong (2011) suggested that excessive exposure to cocaine can produce silent synapses, which can be thought of as a process of metaplasticity. These silent synapses are sites where long term plasticity changes can be induced and maintained (Lee & Dong, 2011). Another study regarding cocaine-induced metaplasticity tested a compound called N-acetylcysteine, which the researchers believed can reverse the effects of cocaine addiction based on the results of other studies (Zhou & Kalivas, 2008; LaRowe et al, 2007). N-acetylcysteine treatment in animal models blocked relapse and reduced self-administration behaviour. In human, it was seen to have stopped craving of cocaine (Moussawi, 2009).

Ultimately, N-acetylcysteine has shown promising results as a drug which prevents the addictive behaviours and relapse. Nonetheless, metaplastivity is a new area of research. While some studies suggest the important role of NMDARs, other studies focus on the roles of AMPARs. This is an ongoing debate waiting to be resolved.

**References**

Abraham, W.C. and Bear, M.F. (1997). Metaplasticity: the plasticity of synaptic plasticity. //Trends Neurosci,// 19(4), 126-130.

Abraham, W.C. and Tate, W.P. (1997). Metaplasticity: a new vista across the field of synaptic plasticity. //Progress in Neurobiology//, 52, 303-323.

Barkus, C. et al. (2009). Hippocampal NMDA receptors and anxiety: at the interface between cognition and emotion. //Eur. J. Pharmacol//, 626, 49–56.

Barria, A. and Malinow, R. (2005). NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII. //Neuron//, 48, 289–301.

Bear, M.F. (1995). Mechanism for a sliding synaptic modification threshold. //Neuron //, **<span style="font-family: 'Calibri','sans-serif';">15 **: 1-4.

Deisseroth, K., Bito, H., Schulman, H., & Tsien, R.W. (1995). A molecular mechanism for metaplasticity. //<span style="font-family: 'Calibri','sans-serif';">Current Biology //, **<span style="font-family: 'Calibri','sans-serif';">5 **(12): 1334-1337.

Huang, Y. Y., et al. (1992). The influence of prior synaptic activity on the induction of long-term potentiation. //Science//, 225(5045), 730-733.

Izumi, Y., Clifford, D.B., & Zorumski, C.F. (1992). Inhibition of long-term potentiation by NMDA-mediated nitric oxide release. //Science//, 257(5074), 1273-1276.

Javitt, D.C. (2004). Glutamate as a therapeutic target in psychiatric disorders. //Mol. Psychiatry//, 9, 984–997.

Kim, J.J. & Diamond, D.M. (2002). The stressed hippocampus, synaptic plasticity and 1132 lost memories. //Nat. Rev. Neurosci//., 3, 453–462.

LaRowe, S.D. et al. (2007). Is cocaine desire reduced by N-acetylcysteine? //Am J Psychiatry,// 164, 1115–1117.

Lee, B.R. and Dong, Y. (2011). Cocaine-induced metaplasticity in the nucleus accumbens: silent synapse and beyond. //Program in Neuroscience//, 61, 1060-1069.

O’Dell, T.J. and Kandel. E.R. (1994). Low-frequency stimulation erases LTP through an NMDA receptor-mediated activation of protein phosphatases. //Learn mem//, 1(2), 129-139.

Ondrejcak, T. et al. (2010). Alzheimer’s disease amyloid beta-protein and synaptic function. //Neuromol.// //Med//, 12, 13–26.

Raymond, C.R. et al. (2000). Metabotropic glutamate receptors trigger homosynaptic protein synthesis to prolong long-term potentiation. //Journal of Neurosci//, 20, 969-976.

<span style="font-family: 'Calibri','sans-serif'; font-size: 14.6667px;">Rufini, S. et al. (2009). Cholesterol depletion inhibits electrophysiological changes induced by anoxia in CA1 region of rat hippocampal slices. //Brain research//, 1298, 178-185.

Sajikumar, S. and Korte, M. (2010). Metaplasticity governs compartmentalization of synaptic tagging and capture through brain-derived neurotrophic factor (BDNF) and protein kinase Mζ (PKMζ). //PNAS//, 108(6), 2551-2556.

<span style="font-family: 'Calibri','sans-serif'; font-size: 14.6667px;">Yang, Y.C. et al. (2003). Focal Adhesion Kinase Is Required, But Not Sufficient, for the Induction of Long-Term Potentiation in Dentate Gyrus Neurons //In Vivo. Journal of Neuroscience,// 23(10), 4072-4080.

<span style="font-family: 'Calibri','sans-serif'; font-size: 14.6667px;">Yashiro, K. and Philpot, B.D. (2008). Regulation of NMDA Receptor subunit expression and its implications for LTD, LTP, and metaplasticity. //Neuropharmacology//, 55(7), 1081-1094.

Zhou, W. and Kalivas, P.W. (2008). N-Acetylcysteine reduces extinction responding and induces enduring reductions in cue- and heroin-induced drug-seeking. //Biological Psychiatry//, 63, 338–340.

Zorumski, C.F. and Izumi, Y. (2012). NMDA receptors and metaplasticity: mechanisms and possible roles in neuropsychiatric disorders. //Neuroscience and biobehavioural reviews//, doi:10.1016.

Zorumski, C.F and Rubin, E.H. (2011). Psychiatry and Clinical Neuroscience: A Primer. Oxford University Press: New York.

<span style="display: block; font-family: 'Calibri','sans-serif'; font-size: 14.6667px; height: 1px; left: -40px; line-height: normal; margin-bottom: 0cm; overflow: hidden; position: absolute; text-indent: 36pt; top: 1293px; width: 1px;"> 1. Bear, M.F. (1995). Mechanism for a sliding synaptic modification threshold. // Neuron //, ** 15 **: 1-4.2. Deisseroth, K., Bito, H., Schulman, H., & Tsien, R.W. (1995). A molecular mechanism for metaplasticity. // Current Biology //, ** 5 **(12): 1334-1337 <span style="display: block; height: 1px; left: -40px; overflow: hidden; position: absolute; top: 2059.5px; width: 1px;">http://neurowiki2012.wikispaces.com/Neurophysiology+of+Learning+and+Memory

<span style="display: block; height: 1px; left: -40px; margin-bottom: 0cm; overflow: hidden; position: absolute; top: 3282.5px; width: 1px;">NMDAR-mediated metaplasticity generates an inhibition of subsequent LTP (by increasing its induction threshold). On the contrary, metabotropic glutamate receptors (mGluR) mediated metaplasticity facilitates the induction of subsequent LTP. mGluR is a G-protein-coupled receptor which activates signaling cascade downstream. The increased induction of LTP by mGluR is mediated by a local synthesis of proteins, which converts the decaying LTP into a stable form of LTP (Raymond et al, 2000). Through the activation of mGluR, protein kinase Mζ (PKMζ) is produced. This protein is a plasticity-related protein, and is associated with the increased induction of LTP (Sajikumar & Korte, 2010). <span style="display: block; height: 1px; left: -40px; margin-bottom: 0cm; overflow: hidden; position: absolute; top: 3282.5px; width: 1px;">Although there have been some studies on this mechanism, it still has not been widely studied. Many current papers suggest that further studies regarding this mechanism are required before proposing a specific pathway.