突触可塑性SynapticPlasticity

1、The Cell Biology of Synaptic PlasticityVictoria M. Ho, Ji-Ann Lee, Kelsey C. Martin 4 NOVEMBER 2011 VOL 334 SCIENCE Kelsey C. Martin Chair, Department of Biological Chemistry, UCLA Communication between the Synapse and the Nucleus during synaptic plasticity in neurons, focusing on:

2、 1) signaling from synapse to nucleus; cargoes, stimulation trigger, pathways 2) mRNA localization and regulated translation. cultured Aplysia sensory-motor neurons and cultured rodent hippocampal neurons cell biological, molecular biological and electrophysiological techniquesSynaptic Plasticity Sy

3、naptic plasticity: process of experience-dependent changes in synaptic connectivity. biological processes, including synaptic vesicle release and recycling, neurotransmitter receptor trafficking, cell adhesion, and stimulus-induced changes in gene expression within neurons excitatory neurons in the

4、mammalian hippocampus long-lasting forms of plasticity that underlie learning and memoryHippocampal Synaptic Plasticity tractable experimental model system: a defined population of identifiable neurons and be amenable to electrophysiological, genetic, and molecular cell biological manipulations. Thr

5、ee sequential synaptic pathways (perforant, mossy fiber, and Schaffer collateral pathways) high-frequency stimuli produce synaptic strengthening called long-term potentiation (LTP); low-frequency stimuli produces synaptic weakening, LTD. LTP and LTD can also be produced by STDP - the relative timing

6、 of pre- and postsynaptic spikes leads to changes in synaptic strengthLTP Mechanistically, 3 component parts: Induction, transient events serving to trigger the formation of LTP. maintenance, persisting biochemical signal. Expression, 指诱导突触传递效能改变的主要参与因素Presynaptic Mechanisms of Plasticity contains s

7、ynaptic vesicles filled with neurotransmitter and a dense matrix of cytoskeleton and scaffolding proteins at the site of release, the active zone Varying the probability of neurotransmitter release: one mechanism for altering synaptic strength during neuronal plasticity vesicle mobilization, docking

8、锚靠，入坞, priming释放前需要进一步的启动反应, fusion融合, and recycling: may be regulated by activitySynapsins and synaptic vesicle mobilizationthree states of synaptic vesicle: The readily releasable pool(RRP), docked at the active zone; The recycling pool, which can be released with moderate stimulation; The reserve

9、 pool(RP), which is only released in response to strong stimuli synapsins tether synaptic vesicles to the actin cytoskeleton and to one another Neuronal stimulation activates kinases phosphorylate synapsins modulate synaptic vesicle tethering alter the number of synaptic vesicles available for relea

10、se Synapsin knockout mice: reserve pools of synaptic vesicles . deficits in learning and memory & various forms of plasticity 内源性激酶和磷酸酶的活性 可能调节phosphorylate synapsins 。RIM proteins and synaptic vesicle docking and priming calcium influx vesicle and plasma membrane soluble NSF-attachment protein rece

11、ptor(SNARE) proteins are brought into close to allow Rab3-interacting molecule (RIM) family RIMs act as scaffolding proteins to cluster calcium channels in the active zone; RIMs tether N- and P/Q-type Ca2+ channels to presynaptic active zones via a direct PDZ-domain-ediated interaction, thereby enab

12、ling fast, synchronous triggering of neurotransmitter release at a synapse and interact with Munc-13 (a priming factor, required for efficient SNARE complex formation and membrane fusion), by binding to Munc13, thereby relieving Munc13 homodimerization promoted vesicle priming PKARIM( ) , RIM1 is re

13、quired for mossy fiber LTP（has a principal presynaptic component）Postsynaptic Mechanisms of Plasticity dendritic spines: postsynaptic compartments the size of the spine head and the volume of the spine correlate with synaptic strength(large spine heads containing more neurotransmitter receptors, ref

14、lecting greater synaptic strength) Spines serve as compartmentalized signaling units, and the number and shape of spines change during synaptic plasticity electron-dense postsynaptic density (PSD): consists of neurotransmitter receptors & an extensive network of scaffolding proteinsPostsynaptic kina

15、ses in the spine: CaMKII and PKM (zeta) LTP and LTD induction are both dependent on postsynaptic Ca2+i LTP requiring large; LTD requiring smaller 先后顺序（PRE/POST; POST/PRE） Ca2+i activates multiple downstream signaling enzymes: the kinases CaMKII and PKCCaMKII（合成调控？） Calcium/calmodulin-dependent prote

16、in kinase II(CaMKII) is a Ca2+-activated enzyme, abundant in the brain, constitutes 12% of the total protein. enriched at synapses, a main protein of the postsynaptic density(PSD) Ca2+-bound calmodulin CaMKII auto Neuronal activity translocates CaMKII to the PSD many PSD proteins, including glutamat

17、e receptors LTP induction(CA1), requires CaMKII activity: transgenic mice lacking the isoform have defective LTP and spatial learning The auto of CaMKII is essential for LTP induction and, perhaps争议, its maintenance（remains activated for at least one hour after LTP） CaMKII is necessary & sufficient

18、for LTP inductionPKM brain-restricted atypical PKC isoform, protein kinase M zeta (PKM) is constitutively active and thus targets without extracellular stimulation PKM mRNA is targeted to dendrites, where activity-dependent signaling cascades regulate its local translation (during LTP and LTD) PKM i

19、s sufficient and necessary? for LTP maintenance and for the maintenance of long-term memories, and PKM activation may perpetuate synaptic plasticity and memoryPKM Late-LTP mainte-nance is reversed by inhibiting PKM, even when inhibitors are applied hours to days after LTP induction；and several forms

20、 of long-term memory are rapidly erased by locally inhibiting PKM in different brain regions of rats and mice, from days to even weeks and months after training the activation of PKM could be maintained for weeks to months only a brief exposure to a PKM inhibitor rapidly disrupt a stable memory tran

21、siently inhibiting PKM pro-duce persistent retrograde memory erasure,with no anterograde effectActivity-dependent modulation of postsynaptic glutamate receptors Glutamate, the main excitatory neurotransmitter in the brain, activates several postsynaptic receptors Two types of ionotropic glutamate re

22、ceptors: a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl D-aspartate (NMDA). ligand-gated ion channels, subserve different phases of synaptic plasticityNMDARs NMDARs, when activated, allow Ca2+i for the induction of LTP. However, NMDARs do not conduct current at resting pote

23、ntials because their channel pores are blocked by magnesium cations. “Coincidence detectors”, to conduct current, they require both presynaptic transmitter release as well as postsynaptic depolarization to relieve the magnesium block STDPAMPARs AMPARs, the expression and maintenance of LTP. Unlike N

24、MDARs, AMPARs can be activated at resting potentials to allow current flow. conductance(through AMPARs) synaptic strength (during NMDAR-dependent LTP at CA1) the mechanisms that regulate their function: changing the open probabilities and conductances of the receptors. unlikely to account for the dr

25、astic changes in AMPAR function seen with LTP. Instead, changes in AMPAR function during synaptic plasticity are mostly due to -induced changes in its abundance at the synapseAMPARs traffic AMPARs traffic (constitutively) to & fromthe plasma membrane via recycling endosomes exocytosis at extrasynapt

26、ic sites, lateral diffusion within the plasma membrane to PSDs, mobility of the receptors receptors diffuse away from the PSD, then undergo clathrin-mediated, dynamin-dependent endocytosis. After endocytosis, small GTP-binding proteins of the Rab family and effector proteins direct AMPARs either to

27、early (sorting) endosomes or back to the plasma membraneStargazin occurs constitutively under basal conditions； and is modulated by activity through changes in actin and myosin dynamics. Stargazin(accessory subunits), mediates the interaction between AMPARs and the PSD protein PSD-95, and this inter

28、action is important for synaptic localization of AMPARs Activity alters the of Stargazin, Stargazin the mobility of AMPARs and enhancing AMPAR function. Blocking Stargazin blocks LTP; Blocking Stargazin de blocks LTD sites of AMPAR AMPARs, tetramers, four subunits, GluA1 through 4. The cytoplasmic t

29、ails of each subunit contain multiple sites that regulate the trafficking of AMPAR PKA of S845 in the long cytoplasmic tail of GluA1 GluA1 surface expression (enhanced insertion and attenuated internalization) LTD de of S845, correlated with the rate of AMPAR endocytosis Knock-in mice with -deficien

30、t mutations at both S831A and S845A: display a loss of NMDA-induced AMPAR internalization, deficits in LTP and LTD, and have impaired spatial memory Activity-dependent modulation of postsynaptic glutamate receptors-Activity-modified residues continue to be discovered Post-translational modifications

31、 at individual sites: regulating GluA1 trafficking and channel properties DO NOT fully account for the changes in GluA1 function the highly conserved T840 site: correlates remarkably well with synaptic strength complex patterns of & other post-translational modifications (e.g.,palmitoylation or ubiq

32、uitination) combine to regulate AMPAR localizationTrans-Synaptic Signaling; the Synaptic Cleft Neurotransmitters diffuse cell adhesion molecules (CAMs), keeps the synapse together. Role of CAMs in synaptic plasticity. Trans-synaptic signaling by retrograde messengers.Role of CAMs in synaptic plastic

33、ity include members of the cadherin, integrin, and immunoglobulin-containing CAMs, as well as neurexins and neuroligins. Regulation of CAMs, experience-dependent Two examples: Neural cell adhesion molecule (NCAM)+ large sialic acid homopolymers polysialylated NCAM (PSA-NCAM) decreases homophilic adh

34、esion to allow new synaptic remodeling and growth PSA-NCAM, promote synaptic remodeling during persistent forms of plasticity Hippocampal learning tasksPSA-NCAM/NCAM inactivation of the enzyme that adds the polysialic moieties blocks hippocampal learning and plasticity Ephrins/ Eph receptors: tyrosi

35、ne kinase. Specific ephrins and Eph receptors Regulate the localization and function of NMDA receptorsTrans-synaptic signaling by retrograde messengers CB1 and CB2 cannabinoid receptors: diffusible, membrane-soluble messengers Ligands: endocannabinoids. modulators of plasticity. inhibitory synapses/

36、excitatory synapses endocannabinoid-LTD(eCB-LTD): Depolarization and activation of a variety of receptorsactivate release of endocannabinoids from the postsynaptic compartment and binding to presynaptic CB receptorssuppression of neurotransmitter release(and thus regulating presynaptic plasticity) E

37、ndocannabinoid signaling :required for extinction/not acquisition of spatial memoriesTrans-synaptic signaling by retrograde messengers both pre- and postsynaptic activity can control eCB-LTD induction two forms of associativity In the postsynaptic compartment, glutamate release and activity-dependen

38、t Ca2+rise facilitate eCB mobilization, a process mediated by PLC. integrate action potential firing which promotes Ca2+ rise and synaptic release of glutamate (Glu) (which activates mGluR-I) facilitate eCB mobilization and eCB-LTD induction PLC operates as a coincidence detector Presynaptic associa

39、tivity involves both CB1R activation by eCBs and presynaptic firing, which increases Ca2+ concentration, thus engaging long-term suppression of transmitter release integrate eCBs which activate presynaptic type 1 cannabinoid receptor (CB1Rs) and presynaptic firing NMDAR may operate as a coincidence

40、detectorThe Tripartite Synapse: Glia and Synaptic Plasticity pre- and postsynaptic compartments, surrounding astrocytes Synaptically localized glia release neuroactive molecules. influence neuronal communication example, release of D-serine (a coactivator of the NMDA receptor) from glia is required

41、for LTP of hippocampal Schaffer collateral synapses Ephrin and Eph receptor signaling between neurons and glia regulates the uptake of glutamate (through glial glutamate transporters) affects neurotransmission and synaptic plasticity Lactate乳酸 from astrocytes, uptake by neurons, be required for long

42、-term hippocampal memory and plasticityRegulating Gene Expression Within Neurons During Plasticity Signaling from synapse to nucleus to regulate transcription. Local protein synthesis. Local protein degradation.Signaling from synapse to nucleus to regulate transcription Fast pathways of signaling to

43、 the nucleus: Ca2+i: voltage- and ligand-gated ion channels（NMDARs, AMPARs） activation of mGluRs(Gq-coupled receptors)Cytosolic calcium can also be released from intracellular pools, Each route of calcium influx induces different programs of gene induction slower pathways of signaling to the nucleus

44、: Soluble signals can also be transported from the synapse to the nucleus by slower, microtubule- and motor proteindependent pathways. Kinases, transcription regulators, 时间延长 transcription factors CREB, MEF2, and Npas4 control the activity-dependent transcription of a large number of down stream act

45、ivity-regulated genesLocal protein synthesis LTP and LTD can occur in a spatially restricted manner: how gene expression in neurons can be limited to subsets of synapses and not generalized to the entire cell? Regulated translation of localized mRNAs Polyribosomes in hippocampal dendrites; dendrites

46、 had been severed from cell bodies found that such dendrites retain the ability to express long-lasting LTP and LTD, indicating that local translation can mediate long-term modification of synaptic strength 图？图？Local protein synthesis- mRNA localization identification of cis-acting RNA elements（bind

47、 to RNA-binding proteins to undergo export from the soma into the dendrite ） no consensus on their sequence or structure RNA binding proteins: Staufen, Zipcode binding protein 1 (ZBP1), and hnRNPA2. Bind cis-acting elements and assemble transcripts into larger RNA transport granulestravel in a kines

48、in-dependent manner along microtubules to their final destination localized RNAs undergo Directed targeting, anchoring, or stabilization?Local protein synthesis- initiation, CPEBactivity-dependent regulation of translation initiation and elongation A mechanism of translational regulation: cytoplasmi

49、c polyadenylation element binding protein (CPEB) CPEB binding to 3 untranslated regions (3UTRs) represses translation CPEB( , activity-dependent manner)recruit other proteins that increase the polyadenylate poly(A) tails of mRNAspoly(A) binding protein (PABP) is recruitedin turn recruits eukaryotic

50、translation initiation factor 4g(eIF4G) to interact with eukaryotic translation initiation factor 4E (eIF4E) to promote translation initiation CPEB regulates translation of dendritically localized CamKII mRNALocal protein synthesis- initiation, 4E-BPs eIF4E-binding proteins (4E-BPs, ) Hypo 4E-BPs bi

51、nd eIF4E and prevent translation initiation Activity ed 4E-BP dissociates from eIF4E and relieves translational inhibition 4E-BP2 knockout mice: E-LTP stimulation protocols could induce L-LTP in brain slices two additional 4E-BPs in neurons: neuroguidin and the cytoplasmic FMRP interacting protein (

52、CYFIP) 4E-BP1 and 2 are believed to affect general translation, these new 4E-BPs may preferentially affect subgroups of transcripts within dendritesLocal protein synthesis- elongation Activity can also regulate translational elongation example: elongation factor: eukaryotic translation elongation factor 2 (eEF2) AP eEF2, translation; spontaneous release of neurotransmitter eEF2, Local effect, indicating that one function of spontaneous release may be to suppress local translation and there by stabilize synapsesLocal pro