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Long-term depression
From Wikipedia, the free encyclopedia
Long-term depression (LTD), in neurophysiology, is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress.[1] LTD in the hippocampus and cerebellum have been the best characterized, but there are other brain areas in which mechanisms of LTD are understood.[1] LTD has also been found to occur in different types of neurons that release various neurotransmitters. It can result from strong synaptic stimulation (as occurs in the cerebellar Purkinje cells) or from persistent weak synaptic stimulation (as in the hippocampus). Long-term potentiation (LTP) is the opposing process to LTD. LTD is thought to result mainly from a decrease in postsynaptic receptor density, although a decrease in presynaptic neurotransmitter 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 on NMDA receptors, metabotrophic glutamate receptors (mGluR), or endocannabinoids.[2] LTD is one of several processes that serves to selectively weaken specific synapses in order to make constructive use of synaptic strengthening caused by LTP. This is necessary because, if allowed to continue increasing in strength, synapses would ultimately reach a ceiling level of efficiency, which would inhibit the encoding of new information.[3]
Contents
1 Neural homeostasis 2 General forms of LTD 3 Mechanisms that weaken synapses 3.1 Hippocampus 3.2 Cerebellum 3.3 Striatum 3.4 Visual cortex 3.5 Prefrontal Cortex 3.6 Perirhinal Cortex 4 Role of endocannabinoids 5 Spike timing-dependent plasticity 6 Motor learning and memory 6.1 Cocaine as a model of LTD in drug addiction 7 Current research 8 See also 9 References 10 External links
Neural homeostasis
It is highly important for neurons to maintain a variable range of neuronal output. If synapses were only reinforced by positive feedback, they would eventually come to the point of complete inactivity or too much
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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] The Bienenstock, Cooper and Munro model (BCM model) proposes that a certain threshold exists such that a level of postsynaptic response below the threshold leads to LTD and above it leads to LTP. BCM theory further proposes that the level of this threshold depends upon the average amount of postsynaptic activity.[6] Scaling has been found to occur when the strength of all of a neurons excitatory inputs are scaled up or down.[7] LTD and LTP coincide with metaplasticity and synaptic scaling to maintain proper neuronal network function.
Cerebellum
LTD occurs at synapses in cerebellar Purkinje neurons, which receive
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two forms of excitatory input, one from climbing fibers and one from parallel fibers. LTD decreases the efficacy of parallel fiber synapse transmission, though, according to recent findings, it also impairs climbing fiber synapse transmission.[3] Both parallel fibers and climbing fibers must be simultaneously activated for LTD to occur. In A model for the mechanisms of one pathway, parallel fiber terminals release glutamate to activate depotentiation and de novo LTD. AMPA and metabotropic glutamate receptors in the postsynaptic Purkinje cell. When 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.[3]
Striatum
The mechanisms of LTD differ in the two subregions of the striatum [1]. LTD is induced at corticostriatal medium spiny neuron synapses in the dorsal striatum by a high frequency stimulus coupled with postsynaptic depolarization, coactivation of dopamine D1 and D2 receptors and group I mGlu receptors, lack of NMDA receptor activation, and endocannabinoid activation.[1] In the prelimbic cortex of the striatum, three forms or LTD have been established.[1] The mechanism of the first is similar to CA1-LTD: a low frequency stimulus induces LTD by activation of NMDA receptors, with postsynaptic depolarization and increased postsynaptic calcium influx.[1] The second is initiated by a high frequency stimulus and is arbitrated by presynaptic mGlu receptor 2 or 3, resulting in a long term reduction in the involvement of P/Q-type calcium channels in glutamate release.[1] The third form of LTD requires endocannabinoids, activation of mGlu receptors, and repetitive stimulation of glutamatergic fibers (13Hz for ten minutes) and results in a long term decrease in presynaptic glutamate release.[1] It is proposed that LTD in GABAergic striatal neurons leads to a long term decrease in inhibitory effects on the basal ganglia, influencing the storage of motor skills.[1]
Visual cortex
Long-term depression has also been observed in the visual cortex, and it is proposed to be involved in ocular dominance.[1] Recurring low-frequency stimulation of layer IV of the visual cortex or the white matter of the visual cortex causes LTD in layer III.[12] In this form of LTD, low-frequency stimulation of one pathway results in LTD only for that input, making it homosynaptic.[12] This type of LTD is similar to that found in the hippocampus, because it is triggered by a small elevation in postsynaptic calcium ions and activation of phosphatases.[12] LTD has also been found to occur in this fashion in layer II.[1] A different mechanism is at work in the LTD that occurs in layer V. In layer V, LTD requires low frequency stimulation, endocannabinoid signaling, and activation of presynaptic NR2B-containing NMDA receptors.[1] It has been found that paired-pulse stimulation (PPS) induces a form of homosynaptic LTD in the superficial layers of the visual cortex when the synapse is exposed to carbachol (CCh) and norepinephrine (NE).[13] The magnitude of this LTD is comparable to that which results from low frequency stimulation, but with fewer stimulation pulses (40 PPS for 900 low frequency stimulations).[13] It is suggested that the effect of NE is to
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control the gain of NMDA receptor-dependent homosynaptic LTD.[13] Like norepinephrine, acetylcholine is proposed to control the gain of NMDA receptor-dependent homosynaptic LTD, but it is likely to be a promoter of additional LTD mechanisms as well.[13]
Prefrontal Cortex
The neurotransmitter serotonin is involved in LTD induction in the prefrontal cortex (PFC). The serotonin system in the PFC plays an important role in regulating cognition and emotion. Serotonin, in cooperation with a group I metabotropic glutamate receptor (mGluR) agonist, facilitates LTD induction through augmentation of AMPA receptor internalization. This mechanism possibly underlies serotonin's role in the control of cognitive and emotional processes that synaptic plasticity in PFC neurons mediates.[14]
Perirhinal Cortex
Computational models predict that LTD creates a gain in recognition memory storage capacity over that of LTP in the perirhinal cortex, and this prediction is confirmed by neurotransmitter receptor blocking experiments.[1] It is proposed that there are multiple memory mechanisms in the perirhinal cortex.[1] The exact mechanisms are not completely understood, however pieces of the mechanisms have been elucidated. Studies suggest that one perirhinal cortex LTD mechanism involves NMDA receptors and I and II mGlu receptors 24 hours after the stimulus.[1] The other LTD mechanism involves acetylcholine receptors and kainate receptors at a much earlier time, about 20 to 30 minutes after stimulus.[1]
Role of endocannabinoids
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 spiketiming-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 receptordependent LTD in the hippocampus.[15]
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endocannabinoid (CB1) receptors and NMDA receptors are stimulated at the same time. Postsynaptic spiking alleviates the Mg2+ block on NMDA receptors. The postsynaptic depolarization will subside by the time an EPSP occurs, enabling Mg2+ to return to its inhibitory binding site. Thus, the influx of Ca2+ in the postsynaptic cell is reduced. CB1 receptors detect postsynaptic activity levels via retrograde endocannabinoid release.[20] STDP selectively enhances and consolidates specific synaptic modifications (signals), while depressing global ones (noise). This results in a sharpened signal-to-noise ratio in human cortical networks that facilitates the detection of relevant signals during information processing in humans.[21]
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tegmental area (VTA), making the dopaminergic neurons in the VTA less likely to fire, and thus resulting in the symptoms of withdrawal.[28]
Current research
Research on the role of LTD in neurological disorders such as Alzheimer's disease (AD) is ongoing. It has been suggested that a reduction in NMDAR-dependent LTD may be due to changes not only in postsynaptic AMPARs but also in NMDARs, and these changes are perhaps present in early and mild forms of Alzheimertype dementia.[29] Additionally, researchers have recently discovered a new mechanism (which involves LTD) linking soluble amyloid beta protein (A) with the synaptic injury and memory loss related to AD. While A's role in LTD regulation has not been clearly understood, it has been found that soluble A facilitates hippocampal LTD and is mediated by a decrease in glutamate recycling at hippocampal synapses. Excess glutamate is a proposed contributor to the progressive neuronal loss involved in AD. Evidence that soluble A enhances LTD through a mechanism involving altered glutamate uptake at hippocampal synapses has important implications for the initiation of synaptic failure in AD and in types of age-related A accumulation. This research provides a novel understanding of the development of AD and proposes potential therapeutic targets for the disease. Further research is needed to understand how soluble amyloid beta protein specifically interferes with glutamate transporters.[30] The mechanism of long-term depression has been well characterized in limited parts of the brain. However, the way in which LTD affects motor learning and memory is still not well understood. Determining this relationship is presently one of the major focuses of LTD research.
See also
Hebbian theory BCM theory Excitatory postsynaptic potential Homeostatic plasticity Inhibitory postsynaptic potential Long-term potentiation (LTP) Spike timing dependent plasticity (STDP) Neural Facilitation (Short-term plasticity) Neuroplasticity Postsynaptic potential Actin remodeling of neurons
References
1. ^ a b c d e f g h i j k l m n o p Massey PV, Bashir ZI (April 2007). "Long-term depression: multiple forms and implications for brain function". Trends Neurosci. 30 (4): 17684. doi:10.1016/j.tins.2007.02.005 (http://dx.doi.org/10.1016%2Fj.tins.2007.02.005) . PMID 17335914 (http://www.ncbi.nlm.nih.gov/pubmed/17335914) . 2. ^ Paradiso MA, Bear MF, Connors BW (2007). Neuroscience: exploring the brain. Hagerstwon, MD: Lippincott Williams & Wilkins. p. 718. ISBN 0-7817-6003-8. 3. ^ a b c d e f g Purves D (2008). Neuroscience (4th ed.). Sunderland, Mass: Sinauer. pp. 197200. ISBN 087893-697-1. 4. ^ Prez-Otao I, Ehlers MD (May 2005). "Homeostatic plasticity and NMDA receptor trafficking". Trends
wikipedia.org//Long-term_depres 6/8
14.11.2010
5. 6.
7.
8.
9.
10. 11.
12. 13.
14.
15.
16.
17.
18.
Neurosci. 28 (5): 22938. doi:10.1016/j.tins.2005.03.004 (http://dx.doi.org/10.1016%2Fj.tins.2005.03.004) . PMID 15866197 (http://www.ncbi.nlm.nih.gov/pubmed/15866197) . ^ Abraham WC, Bear MF (April 1996). "Metaplasticity: the plasticity of synaptic plasticity". Trends Neurosci. 19 (4): 12630. PMID 8658594 (http://www.ncbi.nlm.nih.gov/pubmed/8658594) . ^ Bienenstock EL, Cooper LN, Munro PW (January 1982). "Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex". J. Neurosci. 2 (1): 3248. PMID 7054394 (http://www.ncbi.nlm.nih.gov/pubmed/7054394) . ^ Turrigiano GG, Leslie KR, Desai NS, Rutherford LC, Nelson SB (February 1998). "Activity-dependent scaling of quantal amplitude in neocortical neurons". Nature 391 (6670): 8926. doi:10.1038/36103 (http://dx.doi.org/10.1038%2F36103) . PMID 9495341 (http://www.ncbi.nlm.nih.gov/pubmed/9495341) . ^ a b Escobar ML, Derrick B (2007). "Long-Term Potentiation and Depression as Putative Mechanisms for Memory Formation". In Bermudez-Rattoni F. Neural plasticity and memory: from genes to brain imaging. Boca Raton: CRC Press. ISBN 0-8493-9070-2. ^ a b Bear MF (July 1995). "Mechanism for a sliding synaptic modification threshold" (http://bearlabs1.mit.edu/BearLab/PDFs/bear-.pdf) . Neuron 15 (1): 14. PMID 7619513 (http://www.ncbi.nlm.nih.gov/pubmed/7619513) . http://bearlab-s1.mit.edu/BearLab/PDFs/bear-.pdf. ^ Blanke ML, VanDongen AM (2008). "Activation Mechanisms of the NMDA Receptor". In VanDongen AM. Biology of the NMDA Receptor (Frontiers in Neuroscience). Boca Raton: CRC. ISBN 1-4200-4414-1. ^ Bear MF (April 2003). "Bidirectional synaptic plasticity: from theory to reality" (http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1693164) . Philos. Trans. R. Soc. Lond., B, Biol. Sci. 358 (1432): 64955. doi:10.1098/rstb.2002.1255 (http://dx.doi.org/10.1098%2Frstb.2002.1255) . PMID 12740110 (http://www.ncbi.nlm.nih.gov/pubmed/12740110) . ^ a b c Kirkwood A, Bear MF (May 1994). "Homosynaptic long-term depression in the visual cortex". J. Neurosci. 14 (5 Pt 2): 340412. PMID 8182481 (http://www.ncbi.nlm.nih.gov/pubmed/8182481) . ^ a b c d Kirkwood A, Rozas C, Kirkwood J, Perez F, Bear MF (March 1999). "Modulation of long-term synaptic depression in visual cortex by acetylcholine and norepinephrine". J. Neurosci. 19 (5): 1599609. PMID 10024347 (http://www.ncbi.nlm.nih.gov/pubmed/10024347) . ^ Zhong P, Liu W, Gu Z, Yan Z (September 2008). "Serotonin facilitates long-term depression induction in prefrontal cortex via p38 MAPK/Rab5-mediated enhancement of AMPA receptor internalization" (http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2614015) . J. Physiol. (Lond.) 586 (Pt 18): 446579. doi:10.1113/jphysiol.2008.155143 (http://dx.doi.org/10.1113%2Fjphysiol.2008.155143) . PMID 18653660 (http://www.ncbi.nlm.nih.gov/pubmed/18653660) . ^ Gerdeman GL, Lovinger DM (November 2003). "Emerging roles for endocannabinoids in long-term synaptic plasticity" (http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1574086) . Br. J. Pharmacol. 140 (5): 7819. doi:10.1038/sj.bjp.0705466 (http://dx.doi.org/10.1038%2Fsj.bjp.0705466) . PMID 14504143 (http://www.ncbi.nlm.nih.gov/pubmed/14504143) . ^ a b Jacob V, Brasier DJ, Erchova I, Feldman D, Shulz DE (February 2007). "Spike timing-dependent synaptic depression in the in vivo barrel cortex of the rat". J. Neurosci. 27 (6): 127184. doi:10.1523/JNEUROSCI.426406.2007 (http://dx.doi.org/10.1523%2FJNEUROSCI.4264-06.2007) . PMID 17287502 (http://www.ncbi.nlm.nih.gov/pubmed/17287502) . ^ Markram H, Lbke J, Frotscher M, Sakmann B (January 1997). "Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs". Science 275 (5297): 2135. doi:10.1126/science.275.5297.213 (http://dx.doi.org/10.1126%2Fscience.275.5297.213) . PMID 8985014 (http://www.ncbi.nlm.nih.gov/pubmed/8985014) . ^ Bi GQ, Poo MM (December 1998). "Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type". J. Neurosci. 18 (24): 1046472. PMID 9852584 (http://www.ncbi.nlm.nih.gov/pubmed/9852584) . ^ Feldman DE (July 2000). "Timing-based LTP and LTD at vertical inputs to layer II/III pyramidal cells in rat barrel cortex". Neuron 27 (1): 4556. PMID 10939330 (http://www.ncbi.nlm.nih.gov/pubmed/10939330) . ^ Duguid IC, Smart TG (2008). "Presynaptic NMDA Receptors". In VanDongen AM. Biology of the NMDA Receptor (Frontiers in Neuroscience). Boca Raton: CRC. ISBN 1-4200-4414-1. ^ Kuo MF, Grosch J, Fregni F, Paulus W, Nitsche MA (Dec 2007). "Focusing effect of acetylcholine on neuroplasticity in the human motor cortex" (http://www.jneurosci.org/cgi/content/full/27/52/14442) . The Journal of Neuroscience 27 (52): 144427. doi:10.1523/JNEUROSCI.4104-07.2007
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wikipedia.org//Long-term_depres
14.11.2010
22.
23. 24.
25.
26.
27.
28.
29.
30.
(http://dx.doi.org/10.1523%2FJNEUROSCI.4104-07.2007) . PMID 18160652 (http://www.ncbi.nlm.nih.gov/pubmed/18160652) . http://www.jneurosci.org/cgi/content/full/27/52/14442. ^ a b c d e Bear MF (August 1999). "Homosynaptic long-term depression: a mechanism for memory?" (http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=33710) . Proc. Natl. Acad. Sci. U.S.A. 96 (17): 94578. PMID 10449713 (http://www.ncbi.nlm.nih.gov/pubmed/10449713) . ^ Harnad SR, Cordo P, Bell CC (1997). Motor learning and synaptic plasticity in the cerebellum. Cambridge, UK: Cambridge University Press. ISBN 0-521-59705-6. ^ Aiba A, Kano M, Chen C, Stanton ME, Fox GD, Herrup K, Zwingman TA, Tonegawa S (October 1994). "Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice". Cell 79 (2): 37788. PMID 7954803 (http://www.ncbi.nlm.nih.gov/pubmed/7954803) . ^ Welsh JP, Yamaguchi H, Zeng XH, Kojo M, Nakada Y, Takagi A, Sugimori M, Llins RR (November 2005). "Normal motor learning during pharmacological prevention of Purkinje cell long-term depression" (http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1288000) . Proc. Natl. Acad. Sci. U.S.A. 102 (47): 1716671. doi:10.1073/pnas.0508191102 (http://dx.doi.org/10.1073%2Fpnas.0508191102) . PMID 16278298 (http://www.ncbi.nlm.nih.gov/pubmed/16278298) . ^ a b c Kemp A, Manahan-Vaughan D (March 2007). "Hippocampal long-term depression: master or minion in declarative memory processes?". Trends Neurosci. 30 (3): 1118. doi:10.1016/j.tins.2007.01.002 (http://dx.doi.org/10.1016%2Fj.tins.2007.01.002) . PMID 17234277 (http://www.ncbi.nlm.nih.gov/pubmed/17234277) . ^ a b Manahan-Vaughan D (2005). "Hippocampal Long-Term Depression as a Declarative Memory Mechanism". In Scharfman HE, Stanton PK, Bramham C. Synaptic plasticity and transsynaptic signaling. Berlin: Springer. doi:10.1007/0-387-25443-9_18 (http://dx.doi.org/10.1007%2F0-387-25443-9_18) . ISBN 0387-24008-X. ^ a b c d e f Kauer JA, Malenka RC (November 2007). "Synaptic plasticity and addiction". Nat. Rev. Neurosci. 8 (11): 84458. doi:10.1038/nrn2234 (http://dx.doi.org/10.1038%2Fnrn2234) . PMID 17948030 (http://www.ncbi.nlm.nih.gov/pubmed/17948030) . ^ Min SS, Quan HY, Ma J, Lee KH, Back SK, Na HS, Han SH, Yee JY, Kim C, Han JS, Seol GH (May 2009). "Impairment of long-term depression induced by chronic brain inflammation in rats". Biochem. Biophys. Res. Commun. 383 (1): 937. doi:10.1016/j.bbrc.2009.03.133 (http://dx.doi.org/10.1016%2Fj.bbrc.2009.03.133) . PMID 19341708 (http://www.ncbi.nlm.nih.gov/pubmed/19341708) . ^ Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D (June 2009). "Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake". Neuron 62 (6): 788801. doi:10.1016/j.neuron.2009.05.012 (http://dx.doi.org/10.1016%2Fj.neuron.2009.05.012) . PMID 19555648 (http://www.ncbi.nlm.nih.gov/pubmed/19555648) .
External links
MeSH Long-Term+Synaptic+Depression (http://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi? mode=&term=Long-Term+Synaptic+Depression) Retrieved from "http://en.wikipedia.org/wiki/Long-term_depression" Categories: Memory processes | Neuroscience | Neurology | Neurophysiology This page was last modified on 14 August 2010 at 22:25. Text is available under the Creative Commons Attribution-ShareAlike License; additional terms may apply. See Terms of Use for details. Wikipedia is a registered trademark of the Wikimedia Foundation, Inc., a non-profit organization.
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