User:Patrick.Raab.1/Long-term Depression First Draft

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Not to be confused with chronic depression or Long Depression.

Long-term depression (LTD), in neurophysiology, is the weakening of a neuronal synapse that lasts from hours to days. It results from either strong synaptic stimulation (as occurs in the cerebellar Purkinje cells) or persistent weak synaptic stimulation (as in the hippocampus). Long-term potentiation (LTP) is the opposing process. LTD is thought to result from changes in postsynaptic receptor density, although changes in presynaptic release may also play a role. Cerebellar LTD has been hypothesized to be important for motor learning. However, it is likely that other plasticity mechanisms play a role as well. Hippocampal LTD may be important for the clearing of old memory traces. Hippocampal/cortical LTD can be dependent of NMDA receptors, metabotrophic glutamate receptors (mGluR) or endocannabinoids. LTD is distinct from synaptic depotentiation, which is the reversal of long-term potentiation.[1] LTD is a novel reduction in synaptic strength - specifically, an activity-dependent reduction in the excitatory post-synaptic potential compared to the baseline level.[2]

LTD is one of several processes that serves to selectively weaken explicit sets of synapses in order to make constructive use of synaptic strengthening caused by LTP. This is because, if allowed to continue increasing in strength, synapses would ultimately reach a peak level of efficiency, which would inhibit the encoding of new information.[3]

Long-term Depression and Neural Homeostasis[edit]

It is very important for neurons to maintain a variable range of neuronal output. If synapses were only reinforced by positive feedback, synapses would eventually come to the point of complete inactivity or too much activity. To prevent neurons from becoming static, there are two regulatory forms of plasticity that provide negative feedback: metaplasticity and scaling. [4] Metaplasticity is expressed as a change in the capacity to provoke subsequent synaptic plasticity, including LTD and LTP. [5] Scaling has been found to occur when the strength of all a neuron’s excitatory inputs are scaled up or down. [6] LTD and LTP coincide with metaplasticity and synaptic scaling to maintain proper neuronal network function [7] The Bienenstock, Cooper and Munro model (BMC model) proposes that a certain threshold exists such that a level of post-synaptic response below the threshold leads to LTD and above leads to LTP. BMC theory further proposes that the level of this threshold depends upon the average amount of post synaptic activity. [8]

Types of Long-term Depression[edit]

Homosynaptic LTD[edit]

Homosynaptic LTD is restricted to the individual synapse that is activated by a low frequency stimulus.[7]

Heterosynaptic LTD[edit]

Heterosynaptic LTD occurs at synapses that are not potentiated or are inactive. This form of LTD impacts synapses nearby those receiving action potential.[7]

Associative LTD[edit]

Associative LTD is characterized by the collective presynaptic and postsynaptic increase in intracellular calcium levels.[9]

Mechanism that Weaken the Synapse[edit]

In the Hippocampus[edit]

LTD affects hippocampal synapses between the Schaffer collaterals and the CA1 pyramidal cells. For an LTD to occur at these synapses, Schaffer collaterals must be stimulated repetitively for extended time periods (10-15 minutes) at a low frequency (approximately 1 Hz).[9] Depressed EPSPs result from this particular stimulation pattern. The type of calcium signal in the postsynaptic cell largely determines whether LTD or LTP occurs; LTD is brought about by small, slow rises in postsynaptic calcium levels. Activation of NMDA-type glutamate receptors, which belong to a class of ionotropic glutamate receptors (iGluRs), is required for calcium entry into the CA1 postsynaptic cell.[10] While LTP is in part due to the activation of protein kinases, which subsequently phosphorylate target proteins, LTD arises from activation of calcium-dependent phosphatases that dephosphorylate the target proteins. Selective activation of these phosphatases by varying calcium levels might be responsible for the different effects of calcium observed during LTD.[9] The activation of postsynaptic phosphatases causes internalization of synaptic AMPA receptors (also a type of iGluRs) into the postsynaptic cell by clathrin-coated endocytosis mechanisms, thereby reducing sensitivity to glutamate released by Schaffer collateral terminals.[9]

In the Cerebellum[edit]

LTD occurs at synapses in cerebellar Purkinje neurons, which receive two forms of excitatory input known as climbing fibers and parallel fibers. LTD decreases the efficacy of parallel fiber synapse transmission, though, according to recent findings, it also impairs climbing fiber synapse transmission.[9] Both parallel fibers and climbing fibers must be simultaneously activated for LTD to occur. In one pathway, parallel fiber terminals release glutamate to activate AMPA and metabotropic glutamate receptors in the postsynaptic Purkinje cell. When the glutamate binds to the AMPA receptor, the membrane depolarizes. Glutamate binding to the metabotropic receptors, however, produces diacylglycerol (DAG) and inositol triphosphate (IP3) second messengers. In the pathway initiated by activation of climbing fibers, calcium enters the postsynaptic cell through voltage-gated ion channels, raising intracellular calcium levels. Together, DAG and IP3 augment the calcium concentration rise by targeting IP3-sensitive triggering release of calcium from intracellular stores as well as protein kinase C (PKC) activation (which is accomplished jointly by calcium and DAG). PKC phosphorylates AMPA receptors, causing receptor internalization as is seen in hippocampal LTD. With the loss of AMPA receptors, the postsynaptic Purkinje cell response to glutamate release from parallel fibers is depressed.[9]

In the Visual Cortex[edit]

Long Term Depression has also been observed in the visual cortex. Recurring low-frequency stimulation of layer IV of the visual cortex or the white matter of the visual cortex causes LTD in layer III. [11] In this form of LTD, low-frequency stimulation of one pathway resulted in LTD only for that input, making this type of LTD homosynaptic. [11] This type of LTD is similar to that found in the Hippocampus, it is triggered by a small elevation in postsynaptic calcium ions and activation of phosphatase. [11]

Spike Timing-Dependent Plasticity (STDP)[edit]

STDP refers to the timing of presynaptic and postynaptic action potentials (spikes). STPD is a form of nueral plasticity in which millisecond-scale timing changes in presynaptic and postsynapic spikes can induce LTP and LTD. LTD occurs when postsynaptic spikes lead presynaptic spikes by up to 20-50 ms.[12] Whole-cell patch clamp experiments "in vivo" indicate that post-leading-pre spike delays elicit synaptic depression.[12] LTP is induced when the neurotransmitter release occurs 5-15ms before a back-propagating action potential, and LTD is induced when the stimulus occurs 5-15ms after the bAP. Cite error: The <ref> tag has too many names (see the help page). There is a plasticity window: if the pre-synaptic and post-synaptic spikes are too far apart (i.e. more than 15ms apart), there is little chance of plasticity.[13] The possible window for LTD is wider than that for LTP[14] - although note that this threshold depends on synaptic history.

When postsynaptic action potential firing occurs prior to presynaptic afferent firing, both presynaptic endocannabinoid (CB1) receptors and NMDA receptors are stimulated at the same time. CB1 receptors detect postsynaptic activity levels by retrograde endocannabinoid release, while presynaptic NMDA receptors sense presynaptic spiking. Initial spiking alleviates the Mg2 block on NMDA receptors, whereas further spiking causes the collection of glutamate around the axon terminal and the activation of presynaptic NMDA receptors. [15]

Postsynaptic Calcium Influx and LTD[edit]

Calcium influx in a neuron can cause both LTP and LTD, depending on the timing and frequency of the input[16] The Bienenstock, Cooper and Munro model (BCM model - 1982) explains how the type of Ca2+ signal leads to both LTP and LTD. They postulate that when there is a low calcium influx, it leads to LTD, and a Ca2+ entry above threshold leads to LTP. The threshold level is on a sliding scale, and depends on the history of the synapse. If the synapse has already been subject to LTP, the threshold is raised, increasing the probability that a calcium influx will yield LTD. In this way, it provides a "negative feedback" system to maintain synaptic plasticity.[16]

Ca2+ influx via voltage gated calcium channels (VGCCs) plays an important role in the induction of homosynaptic LTD. LTD is susceptible to manipulations that alter levels of postsynaptic Ca2+ in dendrites.[17]

Associative LTD is dependent on the activation of VGCCs by postsynaptic action potentials. Since the Ca2+ influx through N-type channels is highly regulated, it is a preferred target for neuromodulation by various neurotransmitters such as GABA, glutamate, serotonin, somatostatin, and adenosine. As a result, the recruitment of N-type channels may determine whether the postsynaptic Ca2+ signal is below or above the threshold for LTD induction.[18] Fluorescent imaging studies further indicate that Ca2+ influx via high-threshold L- and R- type VGCCs occurs only when somatic action potentials are generated. The blockage of VGCCs prevents LTD induction.[17]

The Lisman Model[edit]

John Lisman proposed that the concentrations of intracellular Ca2+ have a critical role in determining whether long-term potentiation (LTP) or long-term depression is elicited. This model provides explanation for how the activation of the NMDA (N-methyl-d-aspartate) receptor can both cause depression or potentiation of synaptic transmission. The onset of LTD is a result of weak activation of the NMDA receptor, causing low level increases in Ca2+. Low levels of Ca2+ will result in the activation of the protein phosphatase, calcineurin. [19] Since calcineurin has a greater affinity for Ca2+ then competing protein kinases, it undergoes preferential activation and is responsible for dephosphorylating substrates, resulting in the induction of LTD. Strong activation of the NMDA receptor results in elevated Ca2+ levels and the induction of LTP. [19] The increased concentration of Ca2+ enables the activation of CaMKII and PKC. However, strong NMDA receptor activation results in a feedback inhibition mechanism, preventing LTD.[19]

Role of Endocannabinoids[edit]

Endocannabinoids affect long-lasting plasticity processes in various parts of the brain, serving both as regulators of pathways and necessary retrograde messengers in specific forms of LTD. In regard to retrograde signaling, endocannabinoid receptors (CB1) function widely throughout the brain in presynaptic inhibition. Endocannabinoid retrograde signaling has been shown to effect LTD at corticostriatal synapses and glutamatergic synapses in the prelimbic cortex of the nucleus accumbens (NAc), and it is also involved in spike-timing-dependent LTD in the visual cortex. Endocannabinoids are implicated in LTD of inhibitory inputs (LTDi) within the basolateral nucleus of the amygdala (BLA) as well as in the stratum radiatum of the hippocampus. Additionally, endocannabinoids play an important role in regulating various forms of synaptic plasticity. They are involved in inhibition of LTD at parallel fiber Purkinje neuron synapses in the cerebellum and NMDA receptor dependent LTD in the hippocampus.[20]

The Role of Long-term Depression in Motor learning and Memory[edit]

Long-term depression has long been hypothesized to be an important mechanism behind motor learning and memory. Cerebellar LTD is thought to lead to motor learning and hippocampal LTD is thought to contribute to the decay of memory. Although LTD is now well characterized these hypotheses about its contribution to motor learning and memory remain controversial. [21]

Studies have connected deficient cerebellar LTD with impaired motor learning. In one study, Metabotropic glutamate receptor 1 mutant mice maintain a normal cerebellar anatomy but have weak LTD and consequently impaired motor learning. [22] However, another study on rats and mice proved that normal motor learning occurs while LTD of Purkinje cells is prevented by (1R-1-benzo thiophen-5-yl-2[2-diethylamino)-ethoxy] ethanol hydrochloride (T-588). [23]

Studies on rats have made a connection between LTD and memory. In one study, rats were exposed to a novel environment and homosynaptic LTD in CA1 was observed. [24] After the rats were brought back to their initial environment, LTD activity was lost. It was found that if the rats are exposed to novelty the electrical stimulation required to depress synaptic transmission is of lower frequency than without novelty. [24] When the rat is put in a novel environment, acetylcholine is released in the hippocampus from medial septum fiber resulting in LTD in CA1. [24]

The mechanism of long-term depression has been well characterized. However, how LTD affects motor learning and memory is still not well understood. Understanding this relationship is presently one of the major focuses of LTD research.

References[edit]

Works Cited[edit]

  1. ^ Kandel, E.R., O’Dell, T.J. (1994). "Low-frequency stimulation erases LTP through an NMDA receptor-mediated activation of protein phosphatases". Learning & Memory. 1 (2): 129–139. doi:10.1101/lm.1.2.129.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Bear, Mark F. (2006). Neuroscience: Exploring the Brain. Lippincott Williams & Wilkins. p. 718. ISBN 0781760038, 9780781760034. {{cite book}}: |first2= missing |last2= (help); |format= requires |url= (help); Check |isbn= value: invalid character (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: multiple names: authors list (link) Image of long-term potentiation and long-term depression synaptic strength.
  3. ^ Purves, Dale et. all. (2008). Neuroscience (4 ed.). Sinauer Associates, Inc. pp. 197–200. {{cite book}}: Unknown parameter |city of publication= ignored (help)
  4. ^ Pérez-Otaño, I., Ehlers, M.D. (2005). "Homeostatic plasticity and NMDA receptor trafficking" (PDF). Trends in Neurosciences. 28 (5): 229–238. doi:10.1016/j.tins.2005.03.004. PMID 15866197.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Abraham, W., Bear, M. (1996). "Metaplasticity: plasticity of synaptic plasticity". Trends in Neurosciences. 19 (4): 126–130. doi:10.1016/S0166-2236(96)80018-X. PMID 8658594.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Turrigiano, G.G., Leslie, K.R., Desai, N.S., Rutherford, L.C., Nelson, S.B. (1998). "Activity dependent scaling of quantal amplitude in neocortical neurons". Nature. 391 (6670): 892–896. doi:10.1038/36103. PMID 9495341.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ a b c Escobar, Martha L. and Brian Derrick (2007). [”Long-Term Potentiation and Depression as Putative Mechanisms for Memory Formation” "2"]. In Federico Bermudez-Rattoni (ed.). Neural Plasticity and Memory: From Genes to Brain Imaging. CRC Press, Taylor & Francis Group. {{cite book}}: Check |chapter-url= value (help); Unknown parameter |city of publication= ignored (help)
  8. ^ Bienenstock, E.L., Cooper, L.N., Munro, P.W. (1982). "Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex". The Journal of Neuroscience. 2 (32): 32–48. doi:10.1523/JNEUROSCI.02-01-00032.1982. PMC 6564292. PMID 7054394.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ a b c d e f Purves, Dale et. all. (2008). Neuroscience (4 ed.). Sinauer Associates, Inc. pp. 197–200. {{cite book}}: Unknown parameter |city of publication= ignored (help)
  10. ^ Blanke, Marie L., and Antonius M.J. VanDongen (2007). [“Activation Mechanisms of the NMDA Receptor” "13"]. In Antonius M.J. VanDongen (ed.). Biology of the NMDA Receptor. {{cite book}}: Check |chapter-url= value (help); Unknown parameter |city of publication= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ a b c Bear, M.F., Kirkwood, A. (1994). "Homosynaptic Long-Term Depression in the Visual Cortex". The Journal of Neuroscience. 14 (5): 3404–3412. doi:10.1523/JNEUROSCI.14-05-03404.1994. PMC 6577491. PMID 8182481.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ a b Jacob V., Brasier D. J., Erchova I., Feldman D., Shulz D. (February 2007). "Spike Timing-Dependent Synaptic Depression in the "In Vivo" Barrel Cortex of the Rat". The Journal of Neuroscience. 27 (6): 1271–1284. doi:10.1523/JNEUROSCI.4264-06.2007. PMC 3070399. PMID 17287502.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  13. ^ Bi, Guo-qiang and Mu-ming Poo (1998). > ""Synaptic Modifications in Cultured Hippocampal Neurons: Dependence on Spike Timing, Synaptic Strength, and Postsynaptic Cell Timing"". Journal of Neuroscience. 18 (24): 10464–10472. doi:10.1523/JNEUROSCI.18-24-10464.1998. PMC 6793365. PMID 9852584.
  14. ^ Feldman, D.E. (2000). > ""Timing-based LTP and LTD at vertical inputs to layer II/III pyramidal cells in rat barrel cortex"". Neuron. 27 (1): 45–56. doi:10.1016/s0896-6273(00)00008-8. PMID 10939330.
  15. ^ Duguid, Ian C., Smart, Trevor G. (2007). "Presynaptic NMDA Receptors". In VanDongen, Antonius M. (ed.). Biology of the NMDA Receptor. CRC Press, Taylor & Francis Group. {{cite book}}: |work= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ a b Bear, Mark F. (1995). "Mechanism for a Sliding Synaptic Modification Threshold" (PDF). Neuron. 15 (1): 1–4. doi:10.1016/0896-6273(95)90056-X. PMID 7619513.
  17. ^ a b Christie, B. R., Schexnayder, L. K., Johnston, D. (1997). "Contribution of voltage-gated calcium channels to homosynaptic long-term depression (LTD) in the CA1 region in vitro". J Journal of Neurophysiology. 77 (3): 1651–5. doi:10.1152/jn.1997.77.3.1651. PMID 9084630.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Normann, C., Peckys, C., Schulze, C. H., Walden, J., Jonas, P., Bischofberger, J. (November 2000). "Associative Long-Term Depression in the Hippocampus Is Dependent on Postsynaptic N-Type Ca2+ Channels" (PDF). The Journal of Neuroscience. 20 (22): 8290–7. doi:10.1523/JNEUROSCI.20-22-08290.2000. PMC 6773198. PMID 11069935.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  19. ^ a b c Winder D. G., Sweatt J. D. (July 2001). "Roles of serine/threonine phosphates in hippocampel synaptic plasticity". JNature Reviews Neuroscience. 2 (7): 461–474. doi:10.1038/35081514. PMID 11433371.{{cite journal}}: CS1 maint: date and year (link)
  20. ^ Gerdeman, Gregory L. and David M. Lovinger (September 2003). ""Emerging roles for endocannabinoids in long-term synaptic plasticity"". British Journal of Pharmacology. 140 (5): 781–789. doi:10.1038/sj.bjp.0705466. PMID PMC1574086. Retrieved 23 October 2009. {{cite journal}}: Check |pmid= value (help)CS1 maint: date and year (link)
  21. ^ Bell, C.C., Cordo, P.J., Harnad, S.R., ed. (1997). Motor Learning and Synaptic Plasticity in the Cerebellum. Cambridge University Press. {{cite book}}: Unknown parameter |city of publication= ignored (help)CS1 maint: multiple names: editors list (link)
  22. ^ Aiba, A., Kano, M., Chen, C., Stanton, M.E., Fox, G.D., Herrup, K., Zwingman, T.A., Tonegawa, S. (1994). "Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice". Cell. 79 (2): 377–388. doi:10.1016/0092-8674(94)90205-4.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ^ Kojo, M., Llinas, R.R., Nakada, Y., Sugimori, M., Takagi, A., Welsh, J.P., Yamaguchi, H., Zeng, X. (2005). "Normal motor learning during pharmacological prevention of Purkinje cell long-term depression". PNAS. 102 (47): 17166–17171. doi:10.1073/pnas.0508191102. PMC 1288000. PMID 16278298.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ a b c Bear, M.F. (1999). "Commentary: Homosynaptic long-term depression: A mechanism for memory?". PNAS. 96 (17): 9457–9458. doi:10.1073/pnas.96.17.9457. PMC 33710. PMID 10449713.

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External Links[edit]


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