Sunday, 30 December 2012

Learning and memory

Synaptic plasticity (Wikipedia)
In neurosciencesynaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways.[1] Plastic change also results from the alteration of the number of receptors located on a synapse.[2] There are several underlying mechanisms that cooperate to achieve synaptic plasticity, including changes in the quantity of neurotransmitters released into a synapse and changes in how effectively cells respond to those neurotransmitters.[3] Synaptic plasticity in both excitatory and inhibitory synapses has been found to be dependent upon calcium.[2] Since memories are postulated to be represented by vastly interconnected networks of synapses in the brain, synaptic plasticity is one of the important neurochemical foundations of learning and memory (see Hebbian theory).

Biochemical mechanisms

Two molecular mechanisms for synaptic plasticity (researched by the Eric Kandel laboratories) involve the NMDA and AMPA glutamate receptors. NMDA channel opening (related to level of cellular depolarisation) increases post-synaptic Ca2+ concentration. This is linked to LTP and protein kinase activation. Strong depolarisation of postsynaptic cell completely displacces Mg2+ blocking NMDA ion channels. This allows Ca2+ to enter cell. THis may cause LTP. Weaker depolarisation only partially displaces Mg2+. This causes less Ca2+ entering postsynaptic neuron and lower intracellular Ca2+ concentrations (which activate protein phosphatases and induce long-term depression.
These activated protein kinases serve to phosphorylate post-synaptic excitatory receptors (e.g. AMPA receptors), improving cation conduction, and thereby potentiating the synapse. Also, this signals recruitment of additional receptors into the post-synaptic membrane, and stimulates the production of a modified receptor type, thereby facilitating an influx of calcium. This in turn increases post-synaptic excitation by a given pre-synaptic stimulus. This process can be reversed via the activity of protein phosphatases, which act to dephosphorylate these cation channels.[5]
The second mechanism depends on a second messenger cascade regulating gene transcription and changes in the levels of key proteins at synapses such as CaMKII and PKAII. Activation of the second messenger pathway leads to increased levels of CaMKII and PKAII within the dendritic spine. These protein kinases have been linked to growth in dendritic spine volume and LTP processes such as the addition of AMPA receptors to the plasma membrane and phosphorylation of ion channels for enhanced permeability.[6] Localization or compartmentalization of activated proteins occurs in the presence of their given stimulus which creates local effects in the dendritic spine. Calcium influx from NMDA receptors is necessary for the activation of CaMKII. This activation is localized to spines with focal stimulation and is inactivated before spreading to adjacent spines or the shaft, indicating an important mechanism of LTP in that particular changes in protein activation can be localized or compartmentalized to enhance the responsivity of single dendritic spines. Individual dendritic spines are capable of forming unique responses to presynaptic cells.[7] This second mechanism can be triggered by protein phosphorylation but takes longer and lasts longer, providing the mechanism for long-lasting memory storage. The duration of the LTP can be regulated by breakdown of these second messengersPhosphodiesterase, for example, breaks down the secondary messenger cAMP, which has been implicated in increased AMPA receptor synthesis in the post-synaptic neuron[citation needed].
Long-lasting changes in the efficacy of synaptic connections (long-term potentiation, or LTP) between two neurons can involve the making and breaking of synaptic contacts. Genes such as activin ß-A, which encodes a subunit of activin A, are up-regulated during early stage LTP. The activin molecule modulates the actin dynamics in dendritic spines through the MAP kinase pathway. By changing the F-actin cytoskeletal structure of dendritic spines, spines are lengthened and the chance that they make synaptic contacts with the axonal terminals of the presynaptic cell is increased. The end result is long term maintenance of LTP.[8]
The number of ion channels on the post-synaptic membrane affects the strength of the synapse.[9] Research suggests that the density of receptors on post-synaptic membranes changes, affecting the neuron’s excitability in response to stimuli. In a dynamic process that is maintained in equilibrium, N-methyl D-aspartate receptor (NMDA receptor) and AMPA receptors are added to the membrane by exocytosis and removed by endocytosis.[10][11][12] These processes, and by extension the number of receptors on the membrane, can be altered by synaptic activity.[10][12]Experiments have shown that AMPA receptors are delivered to the synapse through vesicular membrane fusion with the postsynaptic membrane via the protein kinase CaMKII, which is activated by the influx of calcium through NMDA receptors. CaMKII also improves AMPA ionic conductance through phosphorylation.[13] When there is high-frequency NMDA receptor activation, there is an increase in the expression of a protein PSD-95 that increases synaptic capacity for AMPA receptors. This is what leads to a long-term increase in AMPA receptors and thus synaptic strength and plasticity.
If the strength of a synapse is only reinforced by stimulation or weakened by its lack, a positive feedback loop will develop, causing some cells never to fire and some to fire too much. But two regulatory forms of plasticity, called scaling and metaplasticity, also exist to provide negative feedback.[12] Synaptic scaling is a primary mechanism by which a neuron is able to stabilize firing rates up or down.[14]
Synaptic scaling serves to maintain the strengths of synapses relative to each other, lowering amplitudes of small excitatory postsynaptic potentials in response to continual excitation and raising them after prolonged blockage or inhibition.[12] This effect occurs gradually over hours or days, by changing the numbers of NMDA receptors at the synapse (Pérez-Otaño and Ehlers, 2005).Metaplasticity varies the threshold level at which plasticity occurs, allowing integrated responses to synaptic activity spaced over time and preventing saturated states of LTP and LTD. Since LTP and LTD (long-term depression) rely on the influx of Ca2+ through NMDA channels, metaplasticity may be due to changes in NMDA receptors, altered calcium buffering, altered states of kinases or phosphatases and a priming of protein synthesis machinery.[15] Synaptic scaling is a primary mechanism by which a neuron to be selective to its varying inputs.[16] The neuronal circuitry affected by LTP/LTD and modified by scaling and metaplasticity leads to reverberatory neural circuit development and regulation in a Hebbian manner which is manifested as memory, whereas the changes in neural circuitry, which begin at the level of the synapse, are an integral part in the ability of an organism to learn.[17]
There is also a specificity element of biochemical interactions to create synaptic plasticity, namely the importance of location. Processes occur at microdomains – such as exocytosis of AMPA receptors is spatially regulated by the t-SNARE Stx4.[18] Specificity is also an important aspect of CAMKII signaling involving nanodomain calcium.[19] The spatial gradient of PKA between dendritic spines and shafts is also important for the strength and regulation of synaptic plasticity.[6] It is important to remember that the biochemical mechanisms altering synaptic plasticity occur at the level of individual synapses of a neuron. Since the biochemical mechanisms are confined to these "microdomains," the resulting synaptic plasticity affects only the specific synapse at which it took place.

Short-term plasticity

Plasticity can be categorized as short-term, lasting a few seconds or less, or long-term, which lasts from minutes to hours. Short-term synaptic enhancement results from an increase in the probability that synaptic terminals will release transmitters in response to pre-synaptic action potentials. Synapses will strengthen for a short time because of either an increase in size of the readily releasable pool of packaged transmitter or an increase in the amount of packaged transmitter released in response to each action potential.[21] Types of short term plasticity include synaptic augmentation, depression, facilitation, or neural facilitation, and post-tetanic potentiation.

[edit]Synaptic augmentation

Synaptic augmentation is the increased efficacy of synapse lasting in the order of seconds (7 s often quoted). It has been found to be associated with increased efficiency with which action potentials cause release of vesicles containing transmitters.

[edit]Synaptic depression

Synaptic fatigue or depression is usually attributed to the depletion of the readily releasable vesicles. Depression can also arise from post-synaptic processes and from feedback activation of presynaptic receptors.[22] Heterosynaptic depression is thought to be linked to the release of adenosine triphosphate (ATP) from astrocytes.[23]
Stably maintained dendritic spines are associated with lfelong memories by Yang et al
Study on mouse cortex shows that learning and novel sensory experience lead to spine formation and elmination by a protracted process. Extent of spine remodelling correlated with behavioural improvement after learning. A small fraction of new spines induced by novel experience with most psines formed early in development, are preserved and provide structural basis for memory retention. Learning and memory experience leave permanent marks on cortical connections. Sugggests lifelong memories are stored in stable synaptic networks.

Spine dynamics were examined in primary motor cortex after skill learning on an accelerated rotarod. Animals changed gait pattern and learned specific movemements. In forelimb area of motor cortex, increase in dendritic spines in young and adult mice.  Increase not observed in mice running similar distances on slowly moving rotarod and was region specific. Occured in forelimb motor cortex but not barrel cortex. After being trained for 2 days, spien formation is higher if trained with different motor task than if subjected to same training. Motor learning formation not just physical exercise causes spine formation.
a, Transcranial two-photon imaging of spines before and after rotarod training or sensory enrichment. b, CCD camera view of the vasculature of the motor cortex. c, Two-photon image of apical dendrites from the boxed region in b. A higher magnification view of a dendritic segment in c is shown in d. d, e, Repeated imaging of a dendritic branch before (d) and after rotarod training (e). Arrowheads indicate new spines formed over 2 days. f, The percentage of new spines formed within 2 days in the motor cortex was significantly higher in young or adult mice after training as compared with controls with no training or running on a non-accelerated rotarod. No increase in spine formation was found in the barrel cortex after training. g, After previous 2-day training, only a new training regime (reverse running) caused a significant increase in spine formation. h, EE increased spine formation over 2 days in the barrel cortex in both young and adult animals. No significant increase in spine formation was found under EE when the whiskers were trimmed. i, After previous 2-day EE, animals switched to a different EE showed a higher rate of spine formation than those returned to SE. Data are presented as mean ± s.d. *P < 0.005. See Supplementary Table for the number of animals in each group.

Mechanisms of long-term plasticity
Synaptic plasticity, memory and hippocampus: a neural newtork approach to causality by Kerchner and Nicholls
Patient HM suffered from intractable epilepsy. Bilateral removal of medial temporal love and large parts of both hippocampi. He could not form new episodic memories (anterograde amnesia) and loss of old memories (retrograde amnesia).  Hippocampus is essential to form new episodic memories. May have role in longterm storage.

Damage in CA1 region of hippocampus causes anterograde memory impairment in RB. GD became amnesic after bilateral damage in Ca1 region. Medial temporal lobe required to form permanent and usable long-term  memory.

Activation of CaMKII in single dendritic 
spines during long-term potentiation
CaMKII is important in LTP. Lee et al (2009) monitored spatiotemporal dynamics of CAMKII in dendritic spines during LTP.

Silent synapses and the emergence of a postsynaptic mechanism for LTP
A silent synapse is a synapse in which an EPSC is absent at resting membrane potential but becomes apparent on depolarisation. Silent synapses are thought to reflect functional presence of NMDARs but not AMPARs.  As only AMPARs can conudct current at resting membrane potential, absence of functional postsynaptic AMPAs renders a synapse silent. It cannot mediate synpatic transmission under physiological conditions.

It was shown that manipulations used to trigger LTP in hippocampus could also unsilence silent CA1 synapses.

Discovery of silent synapses
A silent synapse is defined as a synapse in which an excitatory postsynaptic current (EPSC) is absent at the resting membrane potential but becomes apparent on depolarization. The traces here were obtained during whole-cell recordings from CA1 pyramidal neurons from acute rat hippocampal slices. a | (From left to right.) High-intensity stimulation evoked a fast, AMPAR-mediated EPSC at a holding potential of -60 mV. When the stimulus intensity was reduced to below the threshold for triggering EPSCs, as shown in a series of superimposed traces from repeated trials, no evoked current appeared at -60 mV. However, using the same stimulus intensity, a slow EPSC did appear at a holding potential of +30 mV; this EPSC disappeared on application of the NMDAR antagonist D-APV, indicating that it was purely mediated by NMDARs. On returning the holding potential to -60 mV, the lower-intensity stimulus again did not evoke a current. The flat traces in this series indicate failures (see Box 2). b | The left-hand panel shows an EPSC appearing at baseline at a holding potential of +55 mV but not at -65 mV. However, after a long-term potentiation protocol, in which stimulation was paired with postsynaptic depolarization to 0 mV, EPSCs appeared at -65 mV (middle panel). As illustrated in the time course graph (right-hand panel), the number of failures diminished markedly after pairing. Part a reproduced, with permission, from Ref. 3 © (1995) Elsevier Science. Part b reproduced, with permission, from Ref. 2 © (1995) Macmillan Publishers Ltd. All rights reserved.

Silent synapsis activation is a proposed mechanism for rapid increases in synaptic efficacy eg  LTP.

Wall and Merrill discovered that some presynaptic stimuli could not trigger postsynaptic firing in spinal cord neurons.

Faber et al studied silent synapses on goldfish Mauthner cell. These giant brainstem neurons mediate escape reflex in fish. They receive inhibitory input from local glycinergic interneurons and excitatory inputs from VIIIth nerve afferent fibres.  Paired recordings from presynaptic interneurons and postsynaptic Mauthner cells showed transmission did not occur in large percentage of cases. Although synapses formed between recorded cells. This may be due to silent synapses.

After postsnyaptic injection of cyclic AMP, synapse unsilencing occurred.  Not in response to direct stimulation of presynaptic fibres by injection of Ca2+ or K+ channel antagonist.

This suggests that glycinergic silent synapses comprise a functional presynaptic bouton and a nonfuntional postsynaptic membrane.

Many VIIIth nerve excitatory synapses onto Mauther cells were silent. Presynaptic injection of K+ channel antaonists unsilenced these synapses. Possibly by enhacing Ca2+ and amplifying triggers for vesicle release. This indicates that in contrast to postynaptiaclly silent glycinergic synapses, these glutamatergic synapses were presynaptically silent.

Although silent synapses are common among different species and different areas of nervous system, mechanisms underlying synaptic silence may vary. Synaptic acitvity triggers unsilencing.

LTP and silent synapses in the hippocampus

Silent synapses was discovered in hippocampal CA1 pyramidal neurons. It was debated whether locus of LTP expression is pre- or postsynaptic. LTP is prototypical model of synaptic plasticity. Coincident presynaptic activity and postsynaptic depolarisation trigger enhanced synaptic transmission. It may be caused by presynaptic increase in glutamate releas or postynaptic increse in responsiveness to glutamate.

Many researchers observed in LTP, AMPAR-mediated EPSC (A-EPSCs) invreased. Little or no increase in NMDAR-mediated EPSCs (N-EPSCs)/

As both receptors colocalise at postsynaptic membrane and bind synaptic glutmate, it is indicated that postsynaptic modification favouring AMPAR activation underlies LTP.

However, theoretically weak presynaptic glutamate release should engage only NMDARs as they bind glutamate with higher affinity than AMPARs. Whereas a more robust signal should activate both types of receptor. Synaptic glutamate concentration peaks quickly after vesicle release. By the time glutamate dissipates by diffusion and uptake, it has not had time to achieve equilibrium with postsynaptic receptors.

Considering NMDARs have slower activation kinetics than AMPARs, apparently affinities of these receptor types converge in these non-equilibrium conditions. It is less likely that glutamate activates NMDARs without a trace of AMPAR activation.

Manipulations that selectively affect presynaptic activity (eg increasing stimulus intensity or applying GABAGB against baclofen, the adenosine antagonist theophylline or phorbol esters, parallel changes in A-EPSCs and N-EPSCS over range of amplitudes broader that amplitudes typical in LTP. LTP did not trigger change in paired pulse facilitation.  Did not seem to involve any change in probability of transmitter release (p).
The minimal magnitude of neurotransmission that can occur at a synapse is the release of a single vesicle of neurotransmitter. Because the amount of neurotransmitter (for example, glutamate) is roughly the same from vesicle to vesicle, the postsynaptic response is graded by quantal steps, the biological principle on which 'quantal analysis' is based. Quantal analysis can be performed most directly by isolating the postsynaptic response to a single quantum of neurotransmitter, typically by blocking action-potential firing with tetrodotoxin (TTX) and waiting for spontaneous, non-action-potential-initiated vesicle release to occur onto a recorded neuron. In this scenario the amplitude, or quantal size (q), of a so-called miniature excitatory postsynaptic current (mEPSC) corresponds to the glutamate sensitivity of the postsynaptic membrane (that is, the number and conductance of its AMPARs), whereas the frequency with which mEPSCs occur is thought to reflect the probability of vesicle release from the presynaptic terminal (p) and the number of release sites (n). (n is probably equivalent to the number of synapses, because most central synapses contain only one release site each.) Quantal content, or ndotp, should represent the total presynaptic output.
Quantal analysis can also be performed on stimulus-evoked EPSCs in the absence of TTX, on the premise that the EPSC is the summation of multiple quanta. If trial-to-trial fluctuations in EPSC amplitude reflect stochastic differences in the number of quanta that are released, then these amplitudes should distribute in a multimodal, quantal manner. According to this simple model, the coefficient of variation (CV) (which is the standard deviation of the EPSC amplitudes normalized to the mean amplitude) varies oppositely with quantal content, and the inverse square, CV-2, is directly proportional to quantal content. As discussed in the text, quantal theory was originally developed in studies of the neuromuscular junction. Because central synapses differ from those at the neuromuscular junction in a number of fundamental ways that go beyond the scope of this Review, some of the assumptions on which quantal theory is based might not apply to glutamatergic synapses (see the references cited in the main text).
At CA1 synapses transmission is quite unreliable, with a p of approximately 0.3; this means that most action potentials do not result in glutamate release (they are 'synaptic failures') and that the ones that are successful rarely result in the release of more than one vesicle. Paired pulse facilitation occurs, in theory, when the Ca2+ influx at a presynaptic bouton has not entirely cleared before the next action potential arrives, resulting in a higher peak presynaptic Ca2+ concentration after this second stimulus than was achieved by the first; a higher Ca2+ concentration increases p and results in the facilitation of the EPSC. Presynaptic Ca2+concentrations quickly return to baseline values, accounting for the limited time window between the first and second stimulus during which paired pulse facilitation can be observed.
Quantal content provides a direct read-out of p in the simplest experimental scenario, in which only one synapse is activated and n = 1 (see figure). But quantal content is not always a faithful presynaptic parameter: in a scenario in which more synapses are sampled in one phase of an experiment than in another (for example, after synapse unsilencing by a long-term potentiation protocol), n will seem to rise, resulting in an increased quantal content even if p remains constant. This increase in n could reflect a true increase in the number of release sites (presynaptic unsilencing) or an increase in the number of functional postsynaptic units that respond to a constant number of release sites (postsynaptic unsilencing); because n does not distinguish between these two possibilities, a change in quantal content — and consequently in CV-2 — cannot be used in isolation as a means to determine whether a change in synaptic strength has a pre- or postsynaptic locus. To take this reasoning one step further, in the scenario in which multiple synapses are activated, some containing both AMPARs and NMDARs and some containing only NMDARs, the quantal content (and thus the CV-2) for AMPAR-mediated EPSCs will seem to be smaller than that for NMDAR-mediated EPSCs21 — a result that would be confusing if these variables were wrongly assumed to reflect only the state of the presynaptic terminal.
On the other hand, it was observed that trial-to-trial variance of EPSC amplitudes declined after LTP. This suggests a presynaptic LTP mechanism. Quantal theory states this reduced variance manifested as decrease in frequency of synaptic failures. (when stimulation does not cause transmission)  and increase in index CV-2 (inverse square of coefficient of variation of EPSC amplitudes).  This reduced variance should correlate with presynaptic changes but not with postsynaptic sensitivity.

Others observed LTP-triggered increases in quantal content (n.p) alone or in concert with increases in quantal size (q).

Contradiction: CV-2 increased after LTP in same experiments in which paired pulse facilitation remained constant. CV-2 seemed to change for A-EPSCs but not N-EPSCs.

Silent synapses is an explanation. By increasing number of active synapses that contribute to EPSCs after LTP has been triggered, synapse unsilencing mimics an increase in n, causing an apparent increase in quantal content and decrease in failure rate. Rise in quantal content would occur with no change in p. This accounts for absence of any change in paired pulse facilitation.

For decades the hippocampus has been a favourite brain structure of neurophysiologists. In part this is because of its central role in the consolidation of new episodic memories, and the hope that studying it will reveal the cellular and molecular mechanisms that underlie learning and memory. Another attractive feature of the hippocampus is its simple, consistent circuitry. Santiago Ramón y Cajal revealed some details of this circuitry in his classic drawing, pictured here in part a of the figure121.
There are three main types of excitatory neurons in the hippocampus: dentate gyrus (DG) granule cells project their axons (mossy fibres) to CA3 pyramidal cells. These CA3 neurons synapse recurrently onto other CA3 neurons and project axons (Schaffer collaterals) to the CA1, where they synapse onto the pyramidal cells there. These CA1 neurons convey the main output of the hippocampus proper.
Nowhere else in the brain has excitatory neurotransmission been more thoroughly described than at the synapses between Schaffer collaterals and the apical dendrites of CA1 pyramidal neurons. At these synapses, multiple types of glutamate receptors coexist (see figure, part b, upper panels), including AMPARs and NMDARs. Both are permeable to Na+ and K+, with reversal potentials close to 0 mV. NMDARs additionally exhibit important interactions with divalent cations: whereas Ca2+ is highly permeant, mediating the important signalling functions of these receptors, Mg2+ gets stuck in the pore, producing voltage-dependent NMDAR blockade at negative membrane potentials (see figure, part b, blue trace in bottom left panel). Thus, at the resting membrane potential (left-hand panels in part b), synaptic glutamate will evoke an excitatory postsynaptic current (EPSC) that is mediated almost entirely by AMPARs (bottom left panel in part b, red trace). Depolarized potentials will relieve the Mg2+ blockade, and EPSCs will subsequently contain contributions from both AMPARs and NMDARs (bottom right panel in partb, black trace). Using selective antagonists to one or the other receptor, these components can be isolated: the AMPAR component is represented by the red trace in the bottom right panel of part b; the NMDAR component is represented by the blue trace in this panel. These traces also highlight the important kinetic differences between the two receptor subtypes: whereas AMPAR-mediated currents activate quickly and decay within milliseconds, NMDAR-mediated currents activate more slowly and decay over hundreds of milliseconds. It should be noted that under physiological conditions the membrane potential of these dendritic spines never reaches positive values. Part a of the figure modified from Ref. 121.
Postsynaptic silence models
Evidence suggests that main mode of synaptic silence is due to absence of postsynaptic AMPARs than impaired presynaptic glutamate release. Pyramidal cell contains a mixture of synapses, some silent and some not, causing lack of control. This might misinterpret data.

Montgomery et al made paired recordings from synaptically connected CA3 neurons. Recuurent CA3 synapses seem to be functionally identical to CA3-CA1 synapses. Authors studied only EPSCs elicited by current injection and action potential generation in presynaptic neuron. This isolated a single defined population of synapses.  

Recordings from some cell pairs showed all-silent synapses that became unsilenced after a pairing protocol. Raising temprature, delivering paired pulses and applying cyclothiazide (positive modulator of AMPAR) did not reveal A-EPSCs at silent synapses.  Each manipulation facilitated A-EPSCs at functional synapses.  N-EPSCs were identical before and after pairing. This indicates unsilencing was not associated in change in glutamate concentration or in speed of glutamate diffusion.  Shows lack of functional postsynaptic AMPARs at silent synapses. Refutes presynaptic mechanism. 

If a large population of hippocampal synapses expresses postynaptic NMDARs but not AMPAR, it could be visualised. Surface AMPARs are absent at some spines. In studies of cultured neurons, a subpopulation of synaptic spines was immunopositive for surface NMDARs but not AMPARs.  Activity triggered rapid appearance of AMPAR immunoreactivity at such spines in an NMDAR-dependent manner. This indicates that synaptic silencing involves physical recruitment of AMPAr.  Electron microscopy of intact tissue showed CA1 spines with immunogold labelling for NMDARs but not AMPARs. Evidence indicates that silent synapses lack AMPARs and that synaptic silencing occurs when AMPARs arrive. 
In hippocampal tissue obtained from young rats, postembedding immunogold labelling was performed using an antibody raised against the carboxyl terminus of the AMPAR subunit GluR1 (a,d,g) or using antibodies that bind to both the GluR2 and the GluR3 subunits (b,c,e,f,h,i); both GluR1 and GluR2 contribute to virtually every tetrameric AMPAR complex in CA1 pyramidal cells. The age at which the tissue was obtained increases from left to right, from postnatal day 2 (P2) to 5 weeks. In each part of the figure, the presynaptic terminals, with glutamate-containing vesicles, are labelled p; opposite each of these terminals is the postsynaptic membrane, marked by the presence of an electron-dense band (the postsynaptic density) where glutamate receptors (black dots) crowd alongside associated anchoring and signalling proteins. A large increase in AMPAR-subunit labelling, relative to the postnatal period, is evident at 5 weeks. Figure reproduced, with permission, from Ref. 96 © (1999) Macmillan Publishers Ltd. All rights reserved.

Silencing the debate
Proof of postsynaptic silencing : preparation is bathed with an inert caged clutamate derivative. One or two-photon laser stimulation is focused on a dendritic spine in a fluorescently labelled nruon. It uncages glutamate. This evokes a single-synapse uncaging-evoked EPSC (uEPSC).

Gluatmate uncaging was used to trigger uEPSCs and thus bypass presynaptic terminal. This paper demonstrated that silent synapses express no functional AMPARs in postsynaptic membrane (Busetto et al 2008).  In acute slices of neonatal rate somatosensory cortex, some spines showed N-uEPSCs but not A-uEPSCs in response to glutamate uncaging. Hypertonic solution applied to such silent spines triggered vesicle fusion at associated presynaptic bouton.This revealed N-EPSCs but not A-EPSCs. AMPAR-silent postynaptic membrane is opposite a fully competent presynaptic terminal.

A CA1 pyramidal neuron projects its large apical dendrite down into the stratum radiatum, where Schaffer collateral axons make en passant synapses onto dendritic spines. The spine pictured on the left is mature, with a full complement of both AMPARs and NMDARs. By contrast, the spine on the right possesses only NMDARs and therefore cannot conduct current in response to presynaptic glutamate release. The expanded view of this silent synapse illustrates how an LTP-induction protocol will cause AMPARs to migrate towards the postsynaptic density, either through lateral diffusion along the synaptic membrane107 or through the fusion of AMPAR-containing endosome
Activation of CaMKII in single dendritic spines during long term potentiation by Lee et al
CaMKII plays a central role in LTP.  Using two-photon fluorescence lifetime imaging microscopy spatiotemporal dynamics of CaMKII was monitored. LTP induction and associated spine enlargement in single spines triggered transient CaMKII activation restricted to stimulated spines. CaMKII in spines was activated by NMDA receptors and L-type voltage sensitive calcium channels by Ca2+ near channels, in response to glutamate uncaging and depolarisation respectively.
Modulation of AMPA receptor unitary conductance by synaptic activity by Benke et al
Benke et al observed that LTP is associated with increase in AMPAR single channel conductance.  Increase in single channel conductance is specific to  LTP. EPSCs were measured.

This may be caused by Ca2+ permeation through NMDA channels, activating kinases and causing incorporation of new repceotrs or modifiction of conductance properties of existing ones. The correlation between the increase in gamma and the baseline gamma indicates that the initial state of the AMPA receptors may determine how synaptic efficiency is altered.
 "The finding that synaptic activity can modify the single channel conductance properties of the AMPA-receptor complement provides a fundamental mechanism for the alteration of synaptic efficiency."
a, Mean EPSCs during baseline and LTP superimposed (left) and scaled (right; expanded timescale). b, All EPSC amplitudes during this experiment. c, Current–variance relationships from baseline (filled circles) and during LTP (open circles) for this cell. Solid lines represent the data fit from which gamma was estimated (for this and all following figures). d, Rise times (20–80%, open circles) and decay times (62%, filled circles) for all EPSCs used for non-SFA. There was no significant change in the variance of rise times and decay times following the induction of LTP (n = 21).
Subunit specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons by Shi et al
A change in AMPA-R-mediated transmission underlies several developmental and adult forms of synaptic plasticity [Bear 1999], [Bliss and Collingridge 1993], [Cline et al. 1996], [Linden and Connor 1995] and [Nicoll and Malenka 1995] that may play important roles in learning and memory (Martin et al., 2000). One proposed mechanism involves an activity-controlled trafficking of AMPA-Rs from nonsynaptic to synaptic sites [Lüscher et al. 2000], [Lynch and Baudry 1984] and [Malinow et al. 2000].
AMPA-Rs are hetero-oligomeric complexes composed of different combinations of four subunits, GluR1 to GluR4 (also referred as GluRA to GluRD) [Dingledine et al. 1999], [Hollmann and Heinemann 1994] and [Seeburg 1993]. Each subunit contains a large extracellular and four membrane-associated domains showing considerable homology among different subunits. In contrast, the cytoplasmic carboxyl termini of these subunits are either long (e.g., GluR1 and GluR4) or short (e.g., GluR2 and GluR3) (Köhler et al., 1994)(Figure 1A). In hippocampus, GluR4 is mainly expressed early in development while GluR1 to GluR3 expression increases with development (Zhu et al., 2000). In adult hippocampus, these three AMPA-R subunits combine to form two distinct populations, GluR1/GluR2 and GluR2/GluR3 (Wenthold et al., 1996). The functional distinction of these two AMPA-R populations or the role played by different carboxyl termini has not been clarified.
Long-term in vivo imaging of experience-dependent snyaptic plasticity in adult cortex
Trachtenberg observed with in vivo omaging that new spines form synapses.
RApid dendritic morphogenesis in CA1 hippocampal dendrites induced by Synpatic plasticity
Activity shapes the structure of neurons and their circuits. Two-photon imaging of CA1 neurons expressing enhanced green fluorescent protein in developing hippocampal slices from rat brains was used to characterize dendritic morphogenesis in response to synaptic activity. High-frequency focal synaptic stimulation induced a period (longer than 30 minutes) of enhanced growth of small filopodia-like protrusions (typically less than 5 micrometers long). Synaptically evoked growth was long-lasting and localized to dendritic regions close (less than 50 micrometers) to the stimulating electrode and was prevented by blockade of N-methyl-d-aspartate receptors. Thus, synaptic activation can produce rapid input-specific changes in dendritic structure. Such persistent structural changes could contribute to the development of neural circuitry.
Dendritic spine changes associated with hippocampal long-term synaptic plasticity by Engert
 Here we combined a local superfusion technique2,3 with two-photon imaging4, which allowed us to scrutinize specific regions of the postsynaptic dendrite where we knew that the synaptic changes had to occur. We show that after induction of long-lasting (but not short-lasting) functional enhancement of synapses in area CA1, new spines appear on the postsynaptic dendrite, whereas in control regions on the same dendrite or in slices where long-term potentiation was blocked, no significant spine growth occurred.
Rapid formation and selective stabilisation of synapses for enduring motor memories by Xu et al
Novel motor skills are learned through repetitive practice and, once acquired, persist long after training stops1, 2. Earlier studies have shown that such learning induces an increase in the efficacy of synapses in the primary motor cortex, the persistence of which is associated with retention of the task3, 4, 5. However, how motor learning affects neuronal circuitry at the level of individual synapses and how long-lasting memory is structurally encoded in the intact brain remain unknown. Here we show that synaptic connections in the living mouse brain rapidly respond to motor-skill learning and permanently rewire. Training in a forelimb reaching task leads to rapid (within an hour) formation of postsynaptic dendritic spines on the output pyramidal neurons in the contralateral motor cortex. Although selective elimination of spines that existed before training gradually returns the overall spine density back to the original level, the new spines induced during learning are preferentially stabilized during subsequent training and endure long after training stops. Furthermore, we show that different motor skills are encoded by different sets of synapses. Practice of novel, but not previously learned, tasks further promotes dendritic spine formation in adulthood. Our findings reveal that rapid, but long-lasting, synaptic reorganization is closely associated with motor learning. The data also suggest that stabilized neuronal connections are the foundation of durable motor memory.

Adaptive regulation of neuronal excitability by a voltage- independent potassium conductance by Brickley et al
Many neurons receive a continuous, or 'tonic', synaptic input, which increases their membrane conductance, and so modifies the spatial and temporal integration of excitatory signals1, 2, 3. In cerebellar granule cells, although the frequency of inhibitory synaptic currents is relatively low, the spillover of synaptically released GABA (gamma-aminobutyric acid)4 gives rise to a persistent conductance mediated by the GABAA receptor5, 6, 7 that also modifies the excitability of granule cells8. Here we show that this tonic conductance is absent in granule cells that lack the alpha6 and delta-subunits of the GABAA receptor. The response of these granule cells to excitatory synaptic input remains unaltered, owing to an increase in a 'leak' conductance, which is present at rest, with properties characteristic of the two-pore-domain K+ channel TASK-1 (refs 9,10,11,12). Our results highlight the importance of tonic inhibition mediated by GABAA receptors, loss of which triggers a form of homeostatic plasticity leading to a change in the magnitude of a voltage-independent K+ conductance that maintains normal neuronal behaviour.

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