Long-term potentiation and SS Lazio: Difference between pages

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{{Football club infobox |

In [[neuroscience]], '''long-term potentiation''' ('''LTP''') is the long-lasting strengthening of the connection between two [[neuron|nerve cells]]. Experimentally, a series of short, high-frequency electric stimulations to a nerve cell [[synapse]] can strengthen, or ''potentiate'', that synapse for minutes to hours. In living cells, LTP occurs naturally and can last from hours to days, months, and years.

clubname = S.S. Lazio |

image = [[Image:Ss_lazio.gif|150px|logo]] |

fullname = Società Sportiva Lazio<br>1900 SpA |

nickname = ''Biancocelesti'' |

founded = [[1900]] |

ground = [[Stadio Olimpico]],<br/>[[Rome]], [[Italy]] |

capacity = 82,656 |

chairman = [[Claudio Lotito]] |

manager = [[Delio Rossi]] |

league = [[Serie A]] |

season = 2004-05 |

position = [[Serie A]], 10th |

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'''S.S. Lazio''' ([[Italian language|Italian]]: ''Società Sportiva Lazio SpA'') is an [[Italy|Italian]] [[football (soccer)|football]] club based in [[Rome]]. They are known as the ''biancocelesti''. They play in light blue shirts, with white shorts and socks.

The biological mehanisms of LTP, largely via the interplay of [[protein kinase]]s, [[phosphatase]]s, and [[gene expression]], give rise to [[synaptic plasticity]] and provide the foundation for a highly adaptable [[nervous system]]. Most neuroscientific [[learning theory|learning theories]] regard LTP and its opposing process, [[long-term depression|LTD]], as the cellular basis of [[learning]] and [[memory]].

The club was founded on January 9th 1900 as Società Podistica Lazio. The name Lazio was taken from the Latin word "Latium", that means "wide", meeting the aim of the founders to symbolize something that includes Rome, but which is not limited to Rome (in fact, Lazio is the name of [[Latium|the region where Rome lies]]). The sky blue and white strip colours were inspired by the [[Greece|Greek]] flag and the country which gave birth to Olympic tradition. At the very beginning of its history, the club ran a number of different sporting activities and, from 1902, the club started the football section.

LTP was discovered in the mammalian [[hippocampus]] by Terje Lømo in [[1966]] and has remained a popular subject of neuroscientific research since. Most modern LTP studies seek to better understand its biology, while other research aims to develop [[drug]]s that exploit these biological mechanisms to treat [[neurodegenerative disease]]s such as [[Parkinson's disease|Parkinson's]] and [[Alzheimer's disease]].

The club did not join the [[Italian Football League|league]] competition until 1913. They made the national decider a number of times but lost, often heavily - 9-1 on aggregate to Casale in 1914 and 6-1 on aggregate to [[Genoa 1893]] in 1923.

== History ==

The club played in the first [[Serie A]], but their highest pre-war finish was second in 1937. Post-war the club continued to fail in the league, but did win the [[Coppa Italia]] in 1958. However, they had to wait until 1974 for their first ''scudetto''.

=== Early theories of learning ===

[[Image:Cajal.jpg|thumb|right|140px|[[Santiago Ramón y Cajal]] proposed that memories might be stored in the connections between nerve cells.]]

However, when [[Sergio Cragnotti]] became president of the club, he was prepared to invest long-term in new players for the club. In 1993 Lazio finished fifth in Serie A, fourth in 1994, second in 1995, third in 1996, and fourth again in 1997 before winning the ''scudetto'' for the second time in 2000 with [[Sven-Göran Eriksson]] (1997-2001) as manager. They had Coppa Italia victories in 1998, 2000 and 2004 and they also won the last UEFA [[Cup Winners' Cup]] in 1999.

By the turn of the 19th century, neurobiologists had good reason to believe that memories were generally not the product of new nerve cell growth. Scientists generally believed that the number of neurons in the adult brain (roughly 10¹¹) did not increase significantly with age. With this realization came the need to explain how memories were created in the absence of new cell growth.

But after a financial scandal which invested Cragnotti and his foodstuff multinational [[Cirio]], Lazio was controlled in 2004 by a bank pool, in order to be sold to enterpreneur [[Claudio Lotito]], who is the current team owner. The new season for Lazio brought away several strong team players, who were sold to make up the big deficit that regarded the team, which is quoted at the ''Piazza Affari'' Italian stock market. During this summer, former 36-year old Lazio star [[Paolo Di Canio]] accepted to join his favourite team one more time, giving up a much more worthwhile contract from his previous team [[Charlton Athletic F.C.|Charlton Athletic]].

Among the first neuroscientists to suggest that learning was not the product of new cell growth was the [[Spain|Spanish]] anatomist [[Santiago Ramón y Cajal]]. In [[1894]] he proposed that memories might be formed by strengthening the connections between existing neurons to improve the effectiveness of their communication. [[Hebbian theory]], introduced by [[Donald Hebb]] in [[1949]], echoed Ramón y Cajal's ideas, and further proposed that cells may grow new connections between each other to enhance their ability to communicate:

The club plays at the 82,656 seater Stadio Olimpico, shared with [[A.S. Roma]]. The two teams play one another each year in the [[Rome derby]], a fiery, emotional match often marked with tension and fights in the stands. The two clubs have a history of rivalry; in the 2003 season an unprecedented event occurred when the [[A.S. Roma|Roma]] [[Ultras]] forced the game to be suspended after false rumours spread around the stadium that a child had been killed by the police prior to the beginning of the game. In the current 2004/2005 season, Lazio won the first leg of the derby 3-1, while the second leg was a 0-0 draw.

:''Let us assume that the persistence or repetition of a reverberatory activity (or "trace") tends to induce lasting cellular changes that add to its stability.... When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased.''{{ref|hebb-org}}

Famous Lazio players include [[Alen Bokšić]], [[Giorgio Chinaglia]], [[Paul Gascoigne]], [[Silvio Piola]], [[Giuseppe Signori]], [[Pavel Nedvěd]], [[Juan Sebastián Verón]], [[Paolo Di Canio]], [[Jaap Stam]], [[Angelo Peruzzi]], [[Hernán Crespo]], [[Dino Baggio]], [[Roberto Mancini]], [[Christian Vieri]] and [[Alessandro Nesta]].

These theories of memory formation were unfortunately foresighted. Neuroscientists were simply not yet equipped with the [[neurophysiology|neurophysiological]] techniques necessary for elucidating the biological underpinnings of learning in animals. These skills would not come until the latter half of the 20th century, at about the same time as the discovery of long-term potentiation.

==First team squad==

=== Discovery of long-term potentiation ===

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[[Image:Hippocampus.png|thumb|right|150px|LTP was first discovered in the rabbit [[hippocampus]]. In humans the hippocampus is located in the medial [[temporal lobe]].]]

'''Goalkeepers'''

*1 {{flagicon|Italy}} [[Angelo Peruzzi]]

LTP was first observed by Terje Lømo in 1966 in the [[Oslo]], [[Norway]], laboratory of Per Andersen{{ref|lomo-discovery}}. There, Lømo conducted a series of [[neurophysiology|neurophysiological]] experiments on [[anesthesia|anesthetized]] rabbits to explore the role of the hippocampus in [[short-term memory]].

*32 {{flagicon|Italy}} [[Marco Ballotta]]

*33 {{flagicon|Italy}} [[Matteo Sereni]]

Isolating the connections between two parts of the hippocampus, the [[perforant pathway]] and [[dentate gyrus]], Lømo observed the electrical changes in the dentate gyrus elicited by stimulation of the perforant pathway. As expected, a single pulse of electrical stimulation to the perforant pathway elicited an [[excitatory postsynaptic potential]] (EPSP) in the dentate gyrus. What Lømo did not expect was that a high-frequency train of stimulation produced larger, prolonged EPSPs compared to the responses evoked by a single stimulus. This phenomenon was soon dubbed "long-term potentiation".

'''Defenders'''

*2 {{flagicon|Italy}} [[Guglielmo Stendardo]]

Timothy Bliss, who joined the Andersen laboratory in [[1968]], collaborated with Lømo in [[1973]] to publish the first characterization of LTP in [[rabbit]] hippocampus.

*5 {{flagicon|Italy}} [[Felice Piccolo]]

*7 {{flagicon|Italy}} [[Manuel Belleri]]

== Types of LTP ==

*8 {{flagicon|Italy}} [[Luciano Zauri]]

*13 {{flagicon|Italy}} [[Sebastiano Siviglia]]

Since its original discovery in the rabbit hippocampus, LTP has been observed in a variety of other neural structures, including the [[cerebral cortex]], [[cerebellum]], [[amygdala]], and many others. The underlying mechanisms of LTP are generally conserved across these different regions, but there are subtle differences in LTP's precise molecular machinery between sites. Very broadly, there are two types of LTP, associative and nonassociative.

*16 {{flagicon|Italy}} [[Andrea Giallombardo]]

*22 {{flagicon|Italy}} [[Massimo Oddo]]

[[Image:Synapse_with_NMDAR_and_AMPAR.png|thumb|left|200px|At rest, the [[NMDA receptor]] is blocked by [[magnesium]], preventing the flow of [[calcium]] into the postsynaptic cell.]]

*25 {{flagicon|Brazil}} [[Emilson Sanchez Cribari|Cribari]]

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=== Associative LTP ===

'''Midfielders'''

*3 {{flagicon|Italy}} [[Roberto Baronio]]

Associative LTP is the molecular analog of associative learning (e.g. [[classical conditioning]]). It is the strengthening of the connection between two neurons that have been simultaneously active. To detect the simultaneous activity of the pre- and postsynaptic cells, associative LTP requires a so-called ''coincidence detector''. In many parts of the brain where associative LTP is observed, the [[NMDA receptor]] (NMDAR) fills the role of coincidence detector. At rest, the NMDAR's calcium channel is blocked by [[magnesium]]; the blockade is relieved only after strong postsynaptic depolarization{{ref|mayer-nmda_mgblock}}. The calcium channel is also [[ligand]]-gated, so that it only opens when presynaptically-released glutamate binds the receptor. When the NMDAR opens, calcium floods the postsynaptic cell triggering associative LTP.

*4 {{flagicon|Italy}} [[Fabio Firmani]]

*6 {{flagicon|France}} [[Ousmane Dabo]]

NMDAR-dependent LTP has been demonstrated in the hippocampus, particularly in the Schaffer collaterals and perforant pathway, and several other brain regions including parts of the amygdala{{ref|rogan-fearcond}} and cerebral cortex{{ref|artola-visualcortex}}.

*10 {{flagicon|Brazil}} [[César Rodríguez Aparecido|Fucking Bitch]]

*20 {{flagicon|Italy}} [[Fabio Liverani]]

There are several types of associative LTP that do not depend on NMDA receptors. NMDAR-independent LTP has been observed, for example, in the amygdala, where it depends instead on [[voltage]]-gated calcium channels{{ref|weisskopf-ca_mediated_ltp}}.

*31 {{flagicon|Denmark}} [[Christian Keller]]

*68 {{flagicon|Italy}} [[Christian Manfredini]]

=== Nonassociative LTP ===

*85 {{flagicon|Switzerland}} [[Valon Behrami]]

*TBD {{flagicon|Belgium}} [[Gaby Mudingayi]]

Nonassociative LTP is brought about by the repeated application of one stimulus (whereas in associative LTP there are at least two stimuli). At nonassociative synapses, such as those involved in [[habituation]] and [[sensitization]], persistent stimulation of the synapse triggers an influx of calcium into the postsynaptic cell. As in associative LTP, calcium signals the beginning of long-term potentiation, but the precise mechanisms of nonassociative LTP are still unknown.

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== Properties of LTP ==

'''Attackers'''

*9 {{flagicon|Italy}} [[Paolo Di Canio]]

NMDA receptor-dependent LTP classically exhibits four main properties: rapid induction, cooperativity, associativity, and input specificity:

*17 {{flagicon|Albania}} [[Igli Tare]]

*18 {{flagicon|Italy}} [[Tommaso Rocchi]]

* LTP can be ''rapidly induced'' by applying one or more ''brief'' [[tetanic stimulation|tetanic stimuli]] to a presynaptic cell. (A tetanic stimulus is a high-frequency sequence of individual stimulati.)

*19 {{flagicon|Macedonia}} [[Goran Pandev]]

* LTP can be induced either by strong tetanic stimulation of a single pathway, or ''cooperatively'' via the weaker stimulation of many. It is explained by the presence of a stimulus threshold that must be reached in order to induce LTP.

*21 {{flagicon|Italy}} [[Simone Inzaghi]]

* ''Associativity'' refers to the observation that when weak stimulation of a single pathway is insufficient for the induction of LTP, simultaneous strong stimulation of another pathway will induce LTP at both pathways. There is some evidence that associativity and cooperativity share the same underlying cellular mechanism (''see [[#Synaptic tagging|Synaptic tagging]]'').

* Once induced, LTP at one synapse is not propagated to adjacent synapses; rather LTP is ''input specific''.

== Phases of LTP ==

LTP is often divided into two phases, an early, protein synthesis-independent phase (E-LTP) that lasts between one and five hours, and a late, [[protein synthesis]]-dependent phase (L-LTP) that lasts from days to months{{ref|lu-nitricoxide}}. Broadly, E-LTP produces short-lived synaptic facilitation by making existing postsynaptic glutamate receptors (e.g. AMPA receptors) more sensitive to glutamate.

Conversely, L-LTP results in a pronounced facilitation of the postsynaptic response largely through the synthesis of new proteins. These proteins include glutamate receptors (e.g. AMPAR), [[transcription factor]]s, and structural proteins that enhance existing synapses and form new connections. There is also considerable evidence that late LTP prompts the postsynaptic synthesis of a retrograde messenger that diffuses to the presynaptic cell increasing the probability of neurotransmitter vesicle release on subsequent stimuli.

=== Early LTP ===

[[Image:LTP_induction.png|thumb|200px|Simultaneous pre- and postsynaptic activity initiates NMDA receptor-dependent LTP.]]

E-LTP can be induced experimentally by applying a few trains of tetanic stimulation to the connection between two neurons{{ref|kandel-tetanization}}. Through normal [[synaptic transmission]], this stimulation causes the release of [[neurotransmitter]]s, particularly [[glutamate]], from the presynaptic terminal onto the postsynaptic cell membrane, where they bind to [[neurotransmitter receptor]]s embedded in the postsynaptic membrane. Though a single presentation of the stimulus is usually not sufficient to induce LTP, repeated presentations cause the postsynaptic cell to be progressively depolarized. In NMDAR-dependent synapses, this progressive depolarization relieves the magnesium blockade of the NMDA receptor. When the next stimulus is applied, glutamate binds the NMDA receptor and calcium floods the postsynaptic cell, rapidly increasing the intracellular concentration of calcium. It is this rapid rise in calcium concentration that induces E-LTP.

Beyond calcium's critical role in the induction of E-LTP, few downstream molecular events leading to the expression and maintenance of E-LTP are known with certainty. Yet there is considerable evidence that E-LTP induction depends upon the activity of several [[protein kinase]]s, including [[calcium/calmodulin-dependent protein kinase II]] (CaMKII), [[protein kinase C]] (PKC) {{ref|kojima-fyn}}{{ref|malinow-pkc_camkii_inhib}}, [[protein kinase A]] (PKA){{ref|otmakhova-camp_inhibition}}, [[mitogen-activated protein kinase]] (MAPK){{ref|english-mapk_required}}{{ref|sweatt-mapk}}, and [[tyrosine kinase]]s{{ref|huang-tyrosinekinase}}.

Postsynaptically, the early phase of LTP is expressed primarily through the enhancement of receptor/channel sensitivity. In NMDA-dependent LTP in the CA1 hippocampus, the endogenous calcium [[chelator]] [[calmodulin]] rapidly binds calcium as a result of NMDAR opening{{ref|malenka-calmodulin_pka}}. The calcium-calmodulin complex directly activates CaMKII which 1) phosphorylates voltage-gated potassium channels increasing their excitability{{ref|sweatt-ltp}}; 2) enhances the activity of existing AMPA receptors; and 3) phosphorylates intracellular AMPARs and activates Syn GAP (a [[Ras GTPase activating protein]]) and the MAPK cascade, facilitating the insertion of AMPARs into the postsynaptic membrane{{ref|esteban-ampa_trafficking}}.

PKA serves a role similar to that of CaMKII, but PKA's effects are more broad. PKA's activity is enhanced during LTP induction by elevated levels of cAMP as a result of calcium's activation of [[adenylyl cyclase]]-1<!--{{ref|otmakhova-camp_inhibition}}-->. Like CaMKII, PKA phosphorylates voltage-dependent potassium channels and also calcium channels enhancing their excitability to future stimuli. Additionally, PKA phosphorylates intracellular AMPAR stores, facilitating their insertion postsynaptically<!--{{ref|esteban-ampa_trafficking}}-->. PKA may also enhance AMPAR delivery via activation of the MAPK cascade<!--{{ref|sweatt-ltp}}-->.

While LTP is induced postsynaptically, it is partially expressed presynaptically. One hypothesis of presynaptic facilitation is that enhanced CaMKII activity during early LTP gives rise to CaMKII autophosphorylation and constitutive activation. Persistent CaMKII activity then stimulates NO synthase, leading to the enhanced production of the putative retrograde messenger, NO. Since NO is a diffusable gas, it freely diffuses across the synaptic cleft to the presynaptic cell leading to a chain of molecular events that facilitate the presynaptic response to subsequent stimuli. (''See [[#Retrograde signaling|Retrograde signaling]] for discussion about the identity of the retrograde messenger.'')

=== Late LTP ===

[[Image:CREB.png|thumb|200px|The late phase of LTP is dependent upon [[gene expression]] and [[protein synthesis]], mediated largely by [[CREB]]-1.]]

Late LTP can be experimentally induced by a series of three or more trains of tetanic stimulation spaced roughly 10 minutes apart. Unlike early LTP, late LTP requires gene transcription{{ref|nguyen-transcription}}{{ref|bourtchuladze-camp-mut}} and protein synthesis{{ref|frey-translation}}, making it an attractive candidate for the molecular analog of long-term memory<!--{{ref|bourtchuladze-camp-mut}}-->.

The synthesis of gene products is driven by kinases which in turn activate [[transcription factor]]s that mediate gene expression. [[cAMP response element binding protein]]-1 (CREB-1) is thought to be the primary transcription factor in the cascade of gene expression that leads to prolonged structural changes to the synapse enhancing its strength{{ref|poser-ac}}. CREB-1 is both necessary{{ref|dash-cre-inj}} and sufficient{{ref|bartsch-creb}} for late LTP. It is active in its phosphorylated form and induces the transcription of so-called ''immediate-early genes'', including [[c-fos]] and [[c-jun]]{{ref|kasahara-pkiv}}. Ultimately, the products of CREB-1-mediated transcription and protein synthesis give rise to new building materials for the synaptic connection between pre- and postsynaptic cell.

During L-LTP, constitutively active CaMKII activates a related kinase, CaMKIV. Additionally, enhanced Ca²⁺ levels during late LTP increase cAMP synthesis via adenylyl cyclase-1, further activating PKA and resulting in the phosphorylation and activation of MAPK{{ref|huang-pka-mapk}}. Facilitated by cAMP, both CaMKII and CaMKIV translocate to the [[cell nucleus]] along with PKA and MAPK (mediated by PKA){{ref|impey-erk-pka}}, where they phosphorylate CREB-1{{ref|segal-creb}}.

There is also some evidence that L-LTP is mediated in part by [[nitric oxide]] (NO){{ref|lu-no}}. In particular, NO may activate [[guanylyl cyclase]], leading to the production of [[cyclic GMP]] and activation [[protein kinase G]] (PKG), which phosphorylates CREB-1. PKG may also cause the release of Ca²⁺ from [[ryanodine receptor]]-gated intracellular stores, increasing the Ca²⁺ concentration which activates other previously mentioned kinase cascades to further activate CREB-1.

== Retrograde signaling ==

Retrograde signalling is a theoretical concept that arises from the question: "If LTP is induced postsynaptically, but expressed presynaptically, how does the presynaptic terminal "know" that LTP has been induced?" The obvious answer is that there must be some communication "backwards" across the synapse, that is, in the retrograde direction from the postsynaptic to the presynaptic side. This concept led to a flurry of work in the early 1990's to demonstrate the existance of a retrograde messenger and also to identify such a messenger. A number of candidates were examined including [[carbon monoxide]]{{ref|alkadhi-retro_co}}, [[platelet-activating factor]]{{ref|kato-retro_paf}}{{ref|kato-retro_paf2}}, arachidonic acid, and nitric oxide{{ref|arancio-retro_no}}{{ref|hawkins-retro_no}}.

Perhaps unfortunately for the retrograde signaling hypothesis, subsequent work has strongly established that LTP, at least early LTP, is expressed entirely postsynaptically (cf. Malenka and Bear, 2004). However, there is still life in the retrograde signalling hypothesis, since it has been demonstrated that ''induction'' of LTP may involve a retrograde messenger, since contrary to dogma, LTP induction does not appear to be entirely postsynaptic (Pavlidis, et al., 2000).

== Synaptic tagging ==

The gene expression and protein synthesis that mediate the long-term changes of LTP generally take place in the cell body, but LTP is synapse-specific; LTP induced at one synapse does not propagate to adjacent inactive synapses. Therefore, the cell is posed with the difficult problem of synthesizing plasticity-related products in the nucleus and cell body, but ensuring they only reach synapses that have received LTP-inducing stimuli.

The synthesis of a "synaptic tag" at a given synapse after LTP-inducing stimuli may serve to capture plasticity-related proteins shipped cell-wide from the nucleus (9020359). Studies of LTP in the [[sea slug|marine snail]] ''[[Aplysia californica]]'' have implicated synaptic tagging as a mechanism for the input-specificity of LTP (9428516)(10535740). Given two widely separated synapses, an LTP-inducing stimulus at one synapse drives several signaling cascades (described previously) that initiates gene expression in the cell nucleus. At the same synapse (but not the unstimulated synapse), local protein synthesis creates a short-lived (less than three hours) synaptic tag (9020359). The products of gene expression are shipped globally throughout the cell, but are only captured by synapses that express the synaptic tag. Thus only the input receiving LTP-inducing stimuli is potentiated, demonstrating LTP's input-specificity.

Synaptic tagging may also give rise to LTP's associativity. If one synapse is excited with LTP-inducing stimulation while a separate synapse is only weakly stimulated, ''both'' synapses will undergo LTP, while weak stimulation alone is insufficient to induce LTP at either synapse. While weak stimuli are unable to induce gene expression in the cell nucleus, they do prompt the synthesis of a synaptic tag. Simultaneous strong stimulation of a separate pathway, capable of inducing nuclear gene expression, then prompts the production of plasticity-related proteins, which are shipped cell-wide. With both synapses expressing the synaptic tag, both capture the protein products resulting in the induction of LTP in both the strongly stimulated and weakly stimulated pathways.

The synaptic tag hypothesis may also explain LTP's cooperativity. While weak stimulation of a single pathway is insufficient to induce LTP, the simultaneous weak stimulation of two pathways is sufficient. As noted previously, weak stimulation initiates the synthesis of a synaptic tag, but is insufficient to trigger late LTP and thus CREB-1-mediated gene expression. But simultaneous weak input converges on kinases that sufficiently activate CREB-1 thereby inducing the synthesis of plasticity-related proteins, which are shipped out cell-wide as described previously. Since a synaptic tag has been synthesized at both synapses, both capture the products of gene expression and both are subsequently potentiated.

== LTP modulation ==

{| border="1" style="border-collapse:collapse;float:right;margin-left:10px" cellpadding="3"

|+ ''LTP modulators, adapted from (10541462).''

|- bgcolor="#cccccc"

! Modulator || Putative target

|-

| [[Dopamine receptor|DA receptors]] || cAMP, MAPK amplification

|-

| [[Adrenergic receptor|&beta;-adrenergic receptor]]s || cAMP, MAPK amplification

|-

| [[Metabotropic GluR|mGluR]] || PKC, MAPK amplification

|-

| [[NO synthase]] || Guanylyl cyclase, PKG, NMDAR

|}

In addition to the signalling pathways described above, hippocampal LTP can be modulated by a variety of molecules. For example, the [[steroid hormone]] [[estradiol]] is one of several molecules that enhances LTP by driving CREB-1 phosphorylation and subsequent [[dendritic spine]] growth (9920677). Additionally, &beta;-adrenergic receptor agonists such as [[norepinephrine]] contribute to the protein synthesis-dependent late phase of LTP (12770561). [[Nitric oxide synthase]] also plays an important role, leading to the up-regulation of nitric oxide and subsequent activation of guanylyl cyclase and PKG, as described previously (10575022). Similarly, activation of [[dopamine receptor]]s enhances LTP via the cAMP/PKA signaling pathway (1833673)(8922403).

== LTP and behavioral memory ==

The mere fact that cultured synapses can undergo long-term potentiation when stimulated by electrodes says little about LTP's relation to memory. Several studies have provided some insight as to whether LTP is a requirement for memory.

=== NMDA blockade ===

Richard Morris provided some of the first evidence that LTP was indeed required for the formation of memories [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2869411]. He tested the [[spatial memory]] of two groups of rats, one whose hippocampi were bathed in the NMDA receptor blocker [[APV]], and the other acting as a control group. (Incidentally, the hippocampus, where LTP was originally observed, is required for spatial learning.) Both groups were then subjected to the [[Morris water maze]], in which rats were placed into a pool of murky water and tested on how quickly they could locate a platform hidden beneath the water's surface.

Rats in the control group were able to locate the platform and escape from the pool, whereas the ability of APV-treated rats to complete the task was significantly impaired. Moreover, when slices of the [[hippocampus]] were taken from both groups of rats, LTP was easily induced in controls, but could not be induced in the brains of APV-treated rats. This provided some evidence that the NMDA receptor &mdash; and thus LTP &mdash; was somehow involved with at least some types of learning and memory.

Similarly, [[Susumu Tonegawa]] has demonstrated that a specific region of the hippocampus, namely CA1, is crucial to the formation of spatial memories [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8980239]. So-called ''[[place cell]]s'' located in this region are responsible for creating "place fields" of the rat's environment, which may be roughly equated with maps of the rat's surroundings. The accuracy of these maps determines how well a rat learns about its environment, and thus how well it can navigate about it.

Tonegawa found that by impairing the NMDA receptor, specifically by [[genetics|genetically]] removing the NMDAR1 subunit in the CA1 region, the place fields generated were substantially less specific than those of controls. That is, rats produced faulty spatial maps when their NMDA receptors were impaired. As expected, these rats performed very poorly on spatial tasks compared to controls, providing more support to the notion that LTP is the underlying mechanism of spatial learning.

=== Doogie mice ===

Enhanced NMDA receptor activity in the hippocampus has also been shown to produce enhanced LTP and an overall improvement in spatial learning. [http://www.bumc.bu.edu/www/busm/pharmacology/tsien/index.htm Joe Tsien] produced a line of [[mus musculus|mice]] with enhanced NMDA receptor function by overexpressing the NR2B subunit in the hippocampus [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11640933]. These smart mice, nicknamed "Doogie mice" after the prodigious doctor [[Doogie Howser]], had larger long-term potentiation and excelled at spatial learning tasks, once again suggesting LTP's involvement in the formation of hippocampal-dependent memories [http://www.abc.net.au/quantum/stories/s103200.htm].

==Team Related topics honors==

*Italian Champions '''2''' 1973/74 1999/00

* [[learning]]

*[[Coppa Italia|Italian Cup]] '''4''' 1958 1997/98 1999/00 2003/04

* [[long-term depression]]

*Italian SuperCup '''1''' 1998

* [[memory]]

*UEFA [[Cup Winners' Cup]] '''1''' 1998/99

*[[European Super Cup]] '''1''' 1999

==NotesExternal links==

*''[http://www.sslazio.it/ Official site]'' (in [[Italian language|Italian]])

#{{note|hebb-org}}{{Book reference | Author=Hebb, D. O. | Title=Organization of Behavior: a Neuropsychological Theory | Publisher=New York: John Wiley | Year=1949 | ID=ISBN 0471367273}}

*[http://www.lazionet.net Lazio.net Community] (Ass. Cult. Lazio.net)

#{{note|lomo-discovery}}{{Journal reference issue | Author=Terje Lømo | Title=The discovery of long-term potentiation | Journal=Philos Trans R Soc Lond B Biol Sci | Volume=358 | Issue=1432 | Year=2003 | Pages=617-20}} PMID 12740104

*[http://www.fcitalia.com/lazio/news/newslazio.htm SS Lazio News] (FC Italia, in Italian)

#{{note|mayer-nmda_mgblock}}{{Journal reference issue | Author=Mayer ML, Westbrook GL, Guthrie PB | Title=Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones | Journal=Nature | Volume=309 | Issue=5965 | Year=1984 | Pages=261-3}} PMID 6325946

*[http://www.laziofever.com LazioFever] The International site in English language about Lazio

#{{note|rogan-fearcond}}{{Journal reference issue | Author=Rogan MT, Staubli UV, LeDoux JE | Title=Fear conditioning induces associative long-term potentiation in the amygdala | Journal=Nature | Volume=390 | Issue=6660 | Year=1997 | Pages=604-7}} PMID 9403688

*[http://www.franciabiancoceleste.com Francia Biancoceleste] (Ultras Lazio, in french)

#{{note|artola-visualcortex}}{{Journal reference issue | Author=Artola A, Singer W | Title=Long-term potentiation and NMDA receptors in rat visual cortex | Journal=Nature | Volume=330 | Issue=6149 | Year=1987 | Pages=649-52}} PMID 2446147

#{{note|weisskopf-ca_mediated_ltp}}{{Journal reference issue | Author=Weisskopf MG, Bauer EP, LeDoux JE | Title=L-type voltage-gated calcium channels mediate NMDA-independent associative long-term potentiation at thalamic input synapses to the amygdala | Journal=J Neurosci | Volume=19 | Issue=23 | Year=1999 | Pages=10512-9}} PMID 10575047

#{{note|lu-nitricoxide}}{{Journal reference issue | Author=Lu YF, Kandel ER, Hawkins RD | Title=Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus | Journal=J Neurosci | Volume=19 | Issue=23 | Year=1999 | Pages=10250-61}} PMID 10575022

#{{note|kandel-tetanization}}{{Journal reference issue | Author=Huang YY, Kandel ER | Title=Recruitment of long-lasting and protein kinase A-dependent long-term potentiation in the CA1 region of hippocampus requires repeated tetanization. | Journal=Learn Mem | Year=1994 | Pages=74-82 | Volume=1 | Issue=1 }} PMID 10467587

#{{note|kojima-fyn}}{{Journal reference issue | Author=Kojima N, Wang J, Mansuy IM, Grant SG, Mayford M, Kandel ER | Title=Rescuing impairment of long-term potentiation in fyn-deficient mice by introducing Fyn transgene | Journal=Proc Natl Acad Sci U S A | Volume=94 | Issue=9 | Year=1997 | Pages=4761-5}} PMID 9114065

#{{note|malinow-pkc_camkii_inhib}}{{Journal reference issue | Author=Malinow R, Schulman H, Tsien RW | Title=Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP | Journal=Science | Volume=245 | Issue=4920 | Year=1989 | Pages=862-6}} PMID 2549638

#{{note|otmakhova-camp_inhibition}}{{Journal reference issue | Author=Otmakhova NA, Otmakhov N, Mortenson LH, Lisman JE | Title=Inhibition of the cAMP pathway decreases early long-term potentiation at CA1 hippocampal synapses | Journal=J Neurosci | Volume=20 | Issue=12 | Year=2000 | Pages=4446-51}} PMID 10844013

#{{note|english-mapk_required}}{{Journal reference issue | Author=English JD, Sweatt JD | Title=A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation | Journal=J Biol Chem | Volume=272 | Issue=31 | Year=1997 | Pages=19103-6}} PMID 9235897

#{{note|sweatt-mapk}}{{Journal reference issue | Author=Sweatt JD | Title=The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory | Journal=J Neurochem | Volume=76 | Issue=1 | Year=2001 | Pages=1-10}} PMID 11145972

#{{note|huang-tyrosinekinase}}{{Journal reference | Author=Huang CC, Hsu KS | Title=Protein tyrosine kinase is required for the induction of long-term potentiation | Journal=J Physiol | Year=1999 | Volume=520 Pt 3 | Pages=783-96}} PMID 10545144

#{{note|malenka-calmodulin_pka}}{{Journal reference issue | Author=Malenka RC, Kauer JA, Perkel DJ, Mauk MD, Kelly PT, Nicoll RA, Waxham MN | Title=An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. | Journal=Nature | Year=1989 | Pages=554-7 | Volume=340 | Issue=6234 }} PMID 2549423

#{{note|sweatt-ltp}}{{Journal reference issue | Author=Sweatt JD | Title=Toward a molecular explanation for long-term potentiation. | Journal=Learn Mem | Year=1999 | Pages=399-416 | Volume=6 | Issue=5 }} PMID 10541462

#{{note|esteban-ampa_trafficking}}{{Journal reference issue | Author=Esteban JA | Title=AMPA receptor trafficking: a road map for synaptic plasticity. | Journal=Mol Interv | Year=2003 | Pages=375-85 | Volume=3 | Issue=7 }} PMID 14993459

#{{note|nguyen-transcription}}{{Journal reference issue | Author=Nguyen PV, Abel T, Kandel ER | Title=Requirement of a critical period of transcription for induction of a late phase of LTP. | Journal=Science | Year=1994 | Pages=1104-7 | Volume=265 | Issue=5175 }} PMID 8066450

#{{note|bourtchuladze-camp-mut}}{{Journal reference issue | Author=Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ | Title=Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. | Journal=Cell | Year=1994 | Pages=59-68 | Volume=79 | Issue=1 }} PMID 7923378

#{{note|frey-translation}}{{Journal reference issue | Author=Frey U, Krug M, Reymann KG, Matthies H | Title=Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro. | Journal=Brain Res | Year=1988 | Pages=57-65 | Volume=452 | Issue=1-2 }} PMID 3401749

#{{note|poser-ac}}{{Journal reference issue | Author=Poser S, Storm DR | Title=Role of Ca2+-stimulated adenylyl cyclases in LTP and memory formation. | Journal=Int J Dev Neurosci | Year=2001 | Pages=387-94 | Volume=19 | Issue=4 }} PMID 11378299

#{{note|dash-cre-inj}}{{Journal reference issue | Author=Dash PK, Hochner B, Kandel ER | Title=Injection of the cAMP-responsive element into the nucleus of Aplysia sensory neurons blocks long-term facilitation. | Journal=Nature | Year=1990 | Pages=718-21 | Volume=345 | Issue=6277 }} PMID 2141668

#{{note|bartsch-creb}}{Journal reference issue | Author=Bartsch D, Casadio A, Karl KA, Serodio P, Kandel ER | Title=CREB1 encodes a nuclear activator, a repressor, and a cytoplasmic modulator that form a regulatory unit critical for long-term facilitation. | Journal=Cell | Year=1998 | Pages=211-23 | Volume=95 | Issue=2 }} PMID 9790528

#{{note|kasahara-pkiv}}{{Journal reference issue | Author=Kasahara J, Fukunaga K, Miyamoto E | Title=Activation of calcium/calmodulin-dependent protein kinase IV in long term potentiation in the rat hippocampal CA1 region. | Journal=J Biol Chem | Year=2001 | Pages=24044-50 | Volume=276 | Issue=26 }} PMID 11306573

#{{note|huang-pka-mapk}}{{Journal reference issue | Author=Huang YY, Martin KC, Kandel ER | Title=Both protein kinase A and mitogen-activated protein kinase are required in the amygdala for the macromolecular synthesis-dependent late phase of long-term potentiation. | Journal=J Neurosci | Year=2000 | Pages=6317-25 | Volume=20 | Issue=17 }} PMID 10964936

#{{note|impey-erk-pka}}{{Journal reference issue | Author=Impey S, Obrietan K, Wong ST, Poser S, Yano S, Wayman G, Deloulme JC, Chan G, Storm DR | Title=Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. | Journal=Neuron | Year=1998 | Pages=869-83 | Volume=21 | Issue=4 }} PMID 9808472

#{{note|segal-creb}}{{Journal reference issue | Author=Segal M, Murphy DD | Title=CREB activation mediates plasticity in cultured hippocampal neurons. | Journal=Neural Plast | Year=1998 | Pages=1-7 | Volume=6 | Issue=3 }} PMID 9920677

#{{note|lu-no}}{{Journal reference issue | Author=Lu YF, Kandel ER, Hawkins RD | Title=Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus. | Journal=J Neurosci | Year=1999 | Pages=10250-61 | Volume=19 | Issue=23 }} PMID 10575022

{{Serie A}}

== References ==

[[Category:Italian football clubs|Lazio]]

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[[Category:Rome|Lazio S.S.]]

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* Hebb, D.O. (1949) The organization of behavior. Wiley, New York.

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