Category:Synaptic Plasticity
INTRODUCTION
NEURAL ANALOGS OF LEARNING AND MEMORY
Neuroscience Origins
It is now generally accepted that many forms of adaptive behavior, including learning and memory, engender lasting physiological changes in the brain; reciprocally, neural plasticity among the brain’s synaptic connections provides the capacity for learning and memory. A major step toward linking synaptic changes with actual instances of learning-related behavioral modification was taken in the 1960s when Eric Kandel published a review entitled “Cellular Neurophysiological Approaches in the Study of Learning”, which emphasized the key to understanding memory formation is through studying neural dynamics at the synaptic level 6. Progress toward these goals wasn’t made, however, until after identifying a simple model organism that displayed adaptive behavior, and pinpointing the neurons involved with this process - Kandel’s team identified a gill withdrawal reflex in Aplysia californium (a sea hare) that could be modified by various forms of conditioning, and then mapped out the sensory and motor neurons involved in this process 5.
After working out these prerequisite issues Kandel and his colleagues were in a position to address many long-standing questions about memory physiology. In a series experiments published in the 1970s, they first detailed the neural correlates of habituation. Applying a mild mechanical or electrical stimulation to an Aplysia’s siphon elicits a pronounced retraction of the gill (i.e. the gill withdrawal reflex) along with excitatory postsynaptic potentials (EPSP) in the gill’s motor neuron; after repeated weak stimulation they found significant reductions in both gill withdrawal and EPSPs lasting for several minutes 7. When this procedure was done for five consecutive days, habituation lasted several weeks 8. Importantly, they could fully mimic these effects when a series of weak stimulations was applied directly to the siphon’s sensory neuron. This is an example of homosynaptic depression, so called because stimulation is applied directly to the pathway being depressed/habituated.
A similar approach was used to characterize sensitization. First they measured baseline gill withdrawal to a weakly stimulated siphon. Then they carried out a behavioral protocol applying a noxious stimulus to the tail, followed by weak stimulation of the siphon, which resulted in greater (sensitized) gill withdrawal compared to baseline 9. They reproduced these effects neurologically by strongly activating a tail interneuron followed by mild activation of a siphon sensory neuron, which resulted in greater gill motor neuron EPSPs and sensitized gill withdrawal 10. Like habituation, when this procedure was repeated across multiple days, sensitization lasted several weeks 11. Sensitization is underlied by heterosynaptic facilitation, as synaptic strength of one pathway (siphon > gill) was enhanced by a second pathway (tail > siphon) 12, 13 (see Fig. 2). In either case of short-term habituation or sensitization, forms of implicit learning, the modulating factor was clearly at the presynaptic terminal, such that after habituation the sensory neuron releases less glutamate neurotransmitter 14, and after sensitization it releases more glutamate neurotransmitter 15. Furthermore it was found that transmitter release was directly regulated by the amount of calcium that entered the presynaptic terminal in response to an action potential 15-17.
Fig. 2: Simplified Neural Circuitry of Aplysia
In subsequent studies conducted in the 1980s and early 1990s, Kandel’s group uncovered the mechanistic difference between short-term and long-term facilitation of this reflex. They found that short term facilitation only required the activation of local proteins like cAMP and PKA that aid in calcium entry into the presynaptic terminal 12, 13, 18. On the other hand, long-term facilitation required the local proteins, in this case PKA and MAPK, to travel up the axon to the nucleus (via retrograde transport) and activate gene transcription factors like CREB 19, 20. New RNA transcripts were then trafficked back down the axon (via anterograde transport) and translated into protein locally at the appropriate terminal, culminating in the growth of new synaptic connections between the sensory and motor neuron 21.
To summarize, these studies revealed that a simple reflex could be modified through learning, and stored as an implicit form of memory. Furthermore, the sensory, motor, and interneurons involved in this reflex circuit could be directly stimulated to reproduce learned behaviors. Perhaps the most striking aspect of these studies was the systematic demonstration that key proteins could be artificially introduced or blocked to precisely mimic natural learning and memory 18. The fundamental breakthrough, however, was that Kandel’s studies provided clear evidence that learning produced changes in synaptic strength, and these changes were a necessary and sufficient component of memory.
POSTSYNAPTIC LONG-TERM POTENTIATION
Fig. 3: Hippocampal Pathways
By the end of the 1980s Kandel’s studies using Aplysia all pointed toward a model where synaptic efficacies are regulated by presynaptic mechanisms; meanwhile the postsynaptic terminal seemed to be a relatively static structure with the purpose of interpreting the quanta of neurotransmitter released by the upstream neuron. However, a limitation of the invertebrate Aplysia model is that neuropsychological inquiries are restricted to simple implicit forms of memory. The mammalian brain, though, has the capacity to store and recall various forms of explicit memory, now thought to require the support of a relatively sophisticated neural circuitry like that found in the mammalian medial-temporal cortex, in a region called the hippocampus.
The hippocampus plays a central role in information integration and spatial memory 22, and its functional integrity is critical for learning and consolidating explicit memory 23. This limbic structure receives afferent projections from entorhinal cortex along the perforant pathway, first enervating granule cells in the dentate gyrus (DG), and continue on with mossy fibers to finally make connections with CA3 pyramidal cells. In turn, CA3 neurons project axons to CA1 pyramidal neurons along the Schaffer collateral pathway, in a final stop before information is routed through the subiculum and looped back to the entorhinal cortex (see Fig 3). All three hippocampal pathways have been used extensively for studying activity-dependent changes in synaptic strength, most notably long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD refer to lasting changes in synaptic efficacies, where LTP is the stable enhancement of synaptic strengths, and LTD is the stable reduction in synaptic strengths. Given these broad definitions, it’s possible for functionally distinct forms of synaptic plasticity to be considered ‘LTP’ 24. Notably, different forms of long-lasting potentiation have been found in the hippocampus itself: at CA3 mossy fiber synapses potentiation is owed to presynaptic mechanisms 25, 26, while potentiation is owed to postsynaptic mechanisms at CA1 Schaffer collateral synapses 27-31. Here I will use the term long-term facilitation (or LTF) when synaptic efficacy-changes are presynaptically mediated (described above in the Aplysia model), and LTP when changes to synaptic efficacy are postsynaptically mediated (consistent with the established convention 13, 24).
The first published observation of LTP, credited to Bliss and Lomo in 1973, was at hippocampal perforant pathway synapses 32. In this study, the authors used an electrode to enervate perforant path axons with short bursts of high-frequency electrical stimulation (100 Hz for ~3 sec), and recorded EPSPs from downstream DG interneurons. This procedure resulted in potentiated connectivity that lasted several hours and was mediated by postsynaptic changes. In this way LTP is analogous to LTF, with three primary exceptions: (1) LTF stems from presynaptic changes while LTP stems from postsynaptic changes, as per definition 4, (2) LTF involves a di-synaptic circuit whereas LTP involves a mono-synaptic circuit 33, and (3) LTF doesn’t require postsynaptic calcium influx while LTP does (re-visited below) 4. Also unlike LTF, LTP has not been so eloquently linked to adaptive behavior; to-date however, LTP remains the most compelling cellular analog of learning and memory in a majority of cortical regions involved in explicit forms of memory 34-36.
Fig. 4: LTP Temporal Dynamics & Effects of Postsynaptic Ca2+
A first step in establishing LTP as an analog of learning was the development of LTP-induction protocols that mimic firing patters during hippocampal-dependent learning. In the pioneering study by Bliss and Lomo, they stimulated neurons at 100 Hz for 3-4 seconds; while neurons do communicate in high-frequency (~100 Hz) “bursts” of action potentials, in vivo bursting activity is brief, only lasts for fractions of a second 37. This disparity prompted research on the development of LTP induction paradigms that were more in-line with innate firing patterns. Ensuing studies revealed that optimal hippocampal LTP induction involves using a priming stimulus followed 100-200 ms later by a brief 100 Hz burst (~10 pulses), in-phase with the ongoing theta rhythm of the hippocampus 38. Indeed, these temporal features of neural firing, together called “theta-bursting”, are typical of CA1 pyramidal neuron activity in rodents during the exploration of space and learning cues 39, 40.
Theta-bursts applied to Schaffer collaterals result in a 3-phase sequence of synaptic potentiation. The short-lasting early phase is referred to as post-tetanic potentiation (PTP), and is mediated by calcium-facilitated release of presynaptic neurotransmitters 41. This initial phase is analogous to long-term facilitation, and its effects decay rapidly as calcium is cleared from the presynaptic terminal over a ~2 min time-course 42. The subsequent phases, known as short-term potentiation (STP) and LTP, generally regarded as two parts of the same phenomenon, depend on the activation of postsynaptic glutamate receptors and calcium (see Fig. 4) 43.
In testing the effects of various compounds on Schaffer pathway transmission, Collingridge et al. (1983) found a pair of compounds that affected excitatory glutamatergic signaling in two functionally different ways: quisqualate globally depressed excitatory transmission, while amino-phosphonovalerate (APV) only blocked potentiation without affecting normal excitatory transmission 43. We now refer to the glutamate receptors that bind those selective antagonists as AMPA-type receptors (AMPAR) and NMDA-type receptors (NMDAR), respectively (after their selective agonist). Building off this and other work 44, Roger Nicoll’s team found that inhibiting postsynaptic calcium entry after a theta-burst fully blocked LTP; conversely, allowing calcium entry into the postsynaptic terminus (even in the absence of a presynaptic stimulus) was sufficient to induce LTP 4. Thus it was discovered that LTP was a postsynaptic process that required NMDAR activation and calcium influx to initiate, and the recruitment of (additional) postsynaptic AMPARs to manifest 45.
AMPA-TYPE GLUTAMATE RECEPTORS (AMPARs)
Hippocampal-dependent memory formation is generally thought to involve changes to the postsynaptic number of AMPARs 28, 29, 46, 47. AMPARs are the primary glutamate receptors that mediate fast-excitatory transmission in the central nervous system, and their expression-level at synapses is directly related to synaptic strength 48. Since their discovery, AMPAR trafficking and regulation has been of acute interest. A variety of electrophysiological and biochemical studies have revealed that AMPARs actively undergo endo/exocytotic exchange between intracellular compartments and the dendritic surface 28, 29, 49, 50, at extrasynaptic membrane locations outside of dendritic spines 51. Relatively recent experiments using techniques like fluorescence recovery after photobleaching (FRAP) and single particle tracking (SPT) methods have established that AMPARs diffuse from extrasynaptic sites into synapses via lateral surface diffusion 52; indeed AMPARs diffuse along the entire dendritic surface, constitutively trafficking in-and-out of synaptic areas 51-53 (see Fig. 5). Thus the quantity of AMPARs in a given synapse is not static, but instead, a dynamic steady-state. Given these exciting new discoveries, a major thrust in today’s work has been geared toward understanding how the cell regulates AMPAR surface diffusion in-and-around synapses, and characterizing AMPAR dynamics from biogenesis through channel conductance.
Fig. 5: AMPAR Surface Diffusion
The AMPAR subunit-family is comprised of four unique subunit proteins, GluR1-GluR4 (aka GluA1-GluA4) that can intermix to form a single AMPAR 54, 55. These 105 kDa-subunits 56 share ~70% gene sequence homology, and may undergo post-transcriptional splicing that results in a long or short version of the intracellular carboxyl-terminus (Ctail) 57 (the implications of having Ctail-variants is discussed below; see Fig. 6a). Before assembling into functional AMPARs, GluR of the same subtype pair-up to form dimers; these dimers then converge with another GluR dimer to form a functional tetrameric AMPAR; thus, AMPARs are considered a ‘dimer of GluR dimers’. The two dimers in an AMPAR can be the same type, yielding a homomeric tetramer (e.g. GluR1-GluR1--GluR1-GluR1), or two different types that yield a heteromeric tetramer (e.g. GluR1-GluR1--GluR2-GluR2). It should be noted however that various factors restrict homomeric AMPARs from assembling in vivo at meaningful quantities (nevertheless, recombinant homomeric AMPARs have been used extensively as molecular probes) 58. Instead, endogenous AMPARs in the hippocampus are almost exclusively heteromeric pairs of GluR1 and GluR2 dimers (GluR1/2), with the remaining AMPARs consisting of GluR2/3 heteromers 59; in both cases GluR2 is present in the receptor. GluR2 pre-mRNA in the adult brain undergoes a “Q/R editing” process that results in the replacement of glutamine (Q) by arginine (R) at the M2 channel segment, yielding (R)-GluR2 60. Aside from gating Na+ in preference for K+, this edit has a fundamentally important consequence: (R)-GluR2 subunits are impermeable to calcium 61. As a result, endogenous AMPAR activation doesn’t itself elicit calcium influx and its associated molecular cascade. Indeed, disrupting Q/R editing has detrimental consequences - mice genetically engineered to express only unedited (Q)-GluR2 develop seizures and die early in development 62.
AMPAR Regulation and Trafficking Overview
Box: Fig. 6: The AMPA-Type Glutamate Receptor
Among the first assessments of the role of AMPARs in LTP was a manipulation that deleted the GluR1 subunit, which blocked hippocampal LTP induction 63. This finding was followed by numerous works focusing on unique properties of the different AMPAR subunits, with particular interest in the GluR Ctail differences. A line of work by Roberto Malinow and colleagues produced a compelling model of AMPAR trafficking during basal and LTP conditions. In this model the GluR2 subunit allows AMPARs to enter basal (non-potentiated) synapses, while the GluR1 subunit promotes synaptic-insertion of AMPARs during LTP 51 — a functional difference shown to depend on properties of their respective Ctails (strikingly, swapping their Ctails swaps their trafficking behavior). A separate line of work focused on the role of AMPAR auxiliary proteins known as transmembrane AMPAR regulatory proteins (TARPs). Similar to the GluR1 deletion, a particular TARP knock-out was found to hinder LTP. This prompted a line of work examining AMPAR regulation during baseline and LTP, with many more experiments aimed at identifying the intracellular binding partners of TARPs and GluR Ctails at synapses. Perhaps unsurprisingly, a variety of subsurface proteins shown to interact with GluR Ctails have recently been implicated in LTP. As it is, the regulation of AMPAR trafficking via Ctail/TARP interactions with synaptic proteins remains a topic of immense interest.
AMPAR Trafficking: GluR Ctails
surface trafficking: AMPARs diffuse laterally along the surface of dendrites and into synapses 64, but before this can happen they must first migrate from the ER to exocytotic zones along the dendrite, and then be inserted into the extrasynaptic membrane 51. Studies have revealed that GluR subtypes have different affinities for surface insertion and synaptic expression, mainly owed to their limited Ctail homology. To address several questions about the contribution of GluR Ctails on surface expression, Granger al’et Nicoll (2013) conducted a study using organotypic CA1 pyramidal cells with an AMPAR-null background (Gria1-3fl/fl [i]) and then expressed recombinant GluR subunits 65. Their experiments showed that membrane insertion of AMPAR is significantly reduced (by ~75%) when the Ctail is removed from GluR1 (GluR1ΔC) compared to full-length GluR1 in the null background. A similar effect was found with GluR2ΔC, in fact, the GluR2 Ctail may be slightly more efficient at promoting surface expression than the GluR1 Ctail 66. That said, there were no appreciable differences in surface levels between full-length GluR1 homomers in the null background vs. AMPAR heteromers in the wild-type cell (as recorded from somatic outside-out patches, or ‘OOPs’) suggesting that GluR1 homomeric AMPARs traffic to the somatic surface just as readily as GluR2-containing AMPAR heteromers.
basal synaptic trafficking: Interestingly, full-length GluR1 expressed in the null background had greatly reduced EPSCs (by 32%) compared to neighboring wild-type cells, suggesting GluR1 homomers don’t accumulate in basal synapses as readily as wild-type heteromers (which all contain GluR2) [ii] 59. As somatic surface expression was the same for recombinant GluR1/1 homomers and wild-type GluR1/2 heteromers, there are only a few ways to explain this finding: (1) GluR2 is important for synaptic insertion at basal synapses; (2) GluR1/1 surface expression only matches GluR1/2 surface expression in the soma and not at dendrites; (3) GluR1 is actively preventing insertion at basal synapses. Interpretation #1 is consistent with a prior study by Makino al’et Malinow (2009) that utilized fluorescence recovery after photobleaching (FRAP) methods — spines with GFP-tagged GluR1 homomers recovered to baseline levels just minutes after photobleaching, indicating that GluR1 quickly diffuses in-and-out of basal spines 51. Conversely, a substantial amount of GluR2 fluorescence (~20%) failed to recover within the 30-min assay, indicative of a slowly-diffusing or trapped fraction of GluR2 homomers in basal spines. Other studies have tested whether these effects are mediated by different binding sequences along the GluR Ctail. Recent work suggests that GluR Ctail sequences are ligands for PDZ domain proteins (further discussed below), and insertion of AMPARs into basal synapses may require the functional integrity of the PDZ-binding segment on the GluR2 Ctail 67 (but see 65). Interestingly, expression of GluR2 dissociated Ctails act as ‘dominant-negatives’ to depress basal transmission while the dissociated Ctail of GluR1 has no effect. Overall these data support a model where GluR2, but not GluR1, promotes receptor accumulation in basal synapses.
LTP synaptic trafficking: As mentioned above, the trafficking profile of GluR subunits change upon LTP induction. In the Makino al’et Malinow (2009) study, both GluR1 and GluR2 homomers showed the same (~20%) non-recovery after chemically-induced LTP, suggesting GluR1 synaptic anchoring ability increases during LTP (while GluR2 anchoring remains constant). The GluR1 Ctail may interact with several synaptic proteins transformed by the LTP signaling cascade, allowing activated synapses to accumulate GluR1-containing AMPARs 68. Indeed, the expression of GluR1 dissociated Ctails can block LTP 67. Perhaps the most striking finding from this work was the discovery that swapping the GluR1 and GluR2 Ctails flip-flops their trafficking profiles 67 -- discriminating evidence that differences in GluR1 and GluR2 trafficking behavior is at least partially mediated by their different Ctails.
AMPAR and SAP Interactions: MAGUK, GRIP, ABP
Fig. 7: MAGUK Proteins
AMPARs are thought to accumulate at synapses by tethering to proteins anchored within the postsynaptic density (PSD). In the mid 1990s a scaffold-associated protein (SAP) called PSD-95, one of the most abundant PSD proteins, was found to interact with glutamate receptors 69. This finding hinted at a role for PSD proteins in regulating synaptic receptor numbers. PSD95 is a member of a superfamily of SAP known as membrane-associated guanylate kinases (MAGUK)[iii], that have a guanylate kinase-like domain (GK), an SH3 domain, and one or more PDZ domains (see Fig. 7). More than 150 proteins have PDZ domain motifs 70, which interact with PDZ-ligand sequences often found on c-terminal peptides, including the Ctail of glutamate receptors (as in Fig. 6b) 71, 72. PDZ-ligands are short amino acid sequences that assist in folding PDZ domains at a β-finger, promoting the assembly of signaling complexes (see Fig. 8). PDZ-domains are common components of scaffolding proteins like MAGUK, and are involved in organizing supramolecular signaling complexes 71 that localize enzymes with their substrates or cluster receptors at biological membranes 73. These clusters form a dense protein scaffolding that ultimately anchors to the actin cytoskeleton.
PDZ interactions, supramolecular clustering, and β-finger folding are complex processes beyond the scope of this review (but see 73 & 74), nonetheless, the emerging role of PDZ-AMPAR interactions represent an exciting new frontier in synaptic plasticity research. Here, I will limit the discussions to a relatively small group PDZ-containing proteins with putative involvement in synaptic plasticity, starting with the Dlg1-4 group of MAGUKs. The Dlg1-4 MAGUK proteins, individually known as SAP97, PSD93, SAP102, and PSD95 (respectively; shown in Fig. 7) are highly expressed at glutamatergic PSDs where they have been implicated in AMPAR synaptic targeting 72, 73. Studies have shown that as the synaptic levels of SAP97, PSD93, or PSD95 increase, so do AMPAR levels 75-79 (with similar, though less dramatic, results have been reported for SAP102 78, 80).
Fig. 8: PDZ Domain Linkage
Given this finding, it’s somewhat inexplicable that SAP97 is the only MAGUK among them known to directly bind AMPARs. Indeed, the GluR1 Ctail directly binds a PDZ domain on SAP97 81, 82 (perhaps involving another synaptic protein called EBP 4.1N 83-85; see Fig. 6b), but to complicate things even further this interaction is shown to happen early in biogenesis, and not at synapses .
While GluR1 is the only subunit known to directly bind a MAGUK Dlg protein, GluR2 is an active binding partner with other PDZ proteins. GluR2 has a consensus sequence (S-V-K-I; see Fig 6a) shown to interact with specific PDZ domains on glutamate receptor interacting proteins (GRIP) 86-88, a splice variant of GRIP called AMPAR binding protein (ABP) 88, 89, and PICK1 90 scaffold proteins. The unique set of synaptic binding partners of GluR1 and GluR2 likely contribute to their different trafficking profiles during basal and potentiated transmission.
Given that (1) PDZ domain proteins help cluster receptors near biological membranes, (2) short carboxyl segments are optimal ligands for PDZ domains, and (3) the overexpression of each Dlg upregulated synaptic AMPARs, one would think GluR Ctails are prime candidates for directly binding the PDZ domain of all four of these MAGUKs. Clearly further study is needed to clarify the mechanism by which PSD93, PSD95, and SAP102 recruit synaptic AMPARs. As it is, there is some evidence that another class of proteins, known as transmembrane AMPAR regulatory proteins (TARPs), contribute to AMPAR trafficking by linking AMPARs to PSD93 and PSD95 MAGUK proteins 91.
TARPs - AMPAR AUXILIARY SUBUNITS
Aside from the interactions between GluR Ctails and MAGUK, there’s evidence that another class of proteins contribute to AMPAR trafficking, known as transmembrane AMPAR regulatory proteins (TARPs) 92, 93. Particular attention has been given to a TARP called stargazin (aka γ2 [iv]). A strain of γ2 knock-out (K.O.) mice called stargazer mice were found to lack the AMPAR-mediated fast-spiking component of mEPSCs[v] in cerebellar neurons, thought to contribute to the stargazer phenotype of absence epilepsy and ataxia. Indeed, granule cells in stargazer cerebellum did not respond to AMPA, even though cellular levels of GluR proteins and mRNA were normal 94, 95. This deficit was shown to be cerebellar-specific, as hippocampal currents were normal in stargazer mice, however the precise role of these stargazin-related TARPs remains controversial (see 96).
A report by Chen et al. (2000) suggested that stargazin/γ2 could associate with AMPARs and bind PSD95 via PDZ interactions 97 (see Fig. 8). This was a provocative finding because GluR Ctails are supposedly incompatable with the PDZ domains of PSD95; so it seemed peculiar that the most abundant synaptic protein, one with PDZ domains perfectly evolved for clustering membrane proteins, didn’t interact with AMPARs [vi]. In the forementioned study, stargazin was shown to co-immunoprecipitate with AMPAR subunits in COS cells - heavily with GluR4, and to a lesser degree, GluR1 and GluR2 [vii]. Chen and coworkers followed this up by expressing recombinant stargazin to the stg-mutant (γ2 knockout) mouse -- they found that full-length stargazin could fully rescuse cerebellar mEPSC[viii], while stargazinΔC (stargazin without the Ctail) rescues only non-synaptic currents in the cerebellum 98. In the hippocampus, expressing stargazinΔC in pyramidal neurons resulted in a marked decrease in both mEPSC amplitude and frequency (suggesting there was both a global reduction total surface AMPARs and a complete loss of AMPARs at some synapses).
Fig. 8: AMPAR - TARP - MAGUK
Together, the experiments above show that cerebellar stargazin promotes AMPAR surface expression and synaptic accumulation, however only for the latter was stargazin’s PDZ domain important. The hippocampal stargazin story is less clear. On one hand, the total absence of stargazin (γ2 K.O.) had no effect on hippocampal EPSCs 95; on the other hand, the insertion of PDZ-lacking stargazin drastically reduced hippocampal mEPSC. What then, is the role of stargazin in the hippocampus?
The hunt to define a functional role of stargazin in the hippocampus, if any, has involved a range of experiments attacking the problem on many fronts. It’s now known that mice express eight stargazin-like proteins (γ1 through γ8), but only four of these isoforms (γ2, γ3, γ4, and γ8) have been show to interact with AMPAR and thus receive the ‘TARP’ designation 98, 99. One or more of the stargazin-family TARPs (γTARPs) bind all four GluR subunits 97, 100, and are found in all major brain regions 101, with γ8 being highly expressed in the hippocampus 98. In a γ8 knock-out model, extrasynaptic AMPARs in hippocampal neurons were drastically reduced, while GluR subunits pooled in the ER 102. In another study, overexpressed GluR1 remained in cell bodies, but when co-expressed with γ2, AMPARs were transported to dendrites 66. It therefore appears AMPAR distribution in hippocampal dendrites relies on γTARPs , suggesting they probably interact with AMPARs during the early stages of biogenesis 98. Indeed, FRET reveals γTARPs are in close proximity to GluR at the ER 103, perhaps assisting in subunit assembly or ER export 98, 104. After leaving the ER, tetrameric GluR complexes enter the Golgi system and are woven through a lipid bilayer to form functional AMPARs 105. Again at this stage, γTARPs may assist in AMPAR membrane-insertion or Golgi export by binding MAP1, a microtubule associated protein important for neurogenesis 106, though a functional corollary of γTARP - MAP1 interaction is lacking.
Two emerging roles for TARPs are (1) the enhancement of AMPAR conductance 96 and (2) protection of AMPAR from proteolysis 107, functions that may be in addition to trafficking roles. Evidence for the modulation of AMPAR biophysical properties comes from studies that exhibit AMPARs co-expressed with stargazin in oocytes, HEK cells, or hippocampal pyramidal neurons have reduced desensitization 66, 108-110, slower deactivation 108, 110, and enhanced recovery 109, 110. One of these studies provided solid evidence that TARPs promote AMPAR dendritic distribution but not surface expression, and also suggested that γ2 could protect against proteolysis. When γ2 was expressed in pyramidal neurons, it selectively prevented GluR1, but not GluR2 lysosomal degredation 66. Furthermore GluR2/3 heteromers were more rapidly digested by trypsin in stargazer extracts than control extracts from cerebellar lysates (it should be noted that GluR1 is not found in adult cerebellar granule neurons) 111. One possible explanation is that poorly assembled multimeric proteins have increased proteolysis susceptibility 112, and if γTARPs help assemble AMPARs, stoichiometric levels between AMPARs and γTARPs must be around 1:1+ for maximal protection. Thus, overexpression of GluR subunits, particularly recombinant subunits, may yield poorly assembeled AMPARs that are targeted for degredation.
DO CTAILS OR TARPS REGULATE AMPAR TRAFFICKING?
From the large body of work one gets the sense that nearly every operative step in the lifetime of an AMPAR depends on Ctails interactions with PDZ and other regulatory proteins, and yet all these same steps seem to involve TARP interactions 114. Moreover, how are subunit-specific trafficking effects observed when TARPs lack subunit specificity 115? The most straightforward answer would be if TARPs complex with AMPARs early on in biogenesis, where aid in tetramer formation, ER export, cytosolic transport, and surface expression. After the TARP-AMPAR complex reaches the surface they dissociated and part ways. Alternatively, the reverse scenario may be true, where MAGUK proteins help along the secretory pathway, transitioning AMPARs from the ER and Golgi systems out to dendritic arbors. As mentioned above, SAP97 is known to associate with GluR1 to a much greater extent in these organelles than at synapses 86. However, this may change later in development, after various other subunit-specific binding proteins like GRIP and ABP mobilize into synapses to accommodate subunit-specific trafficking (reviewed in 94). As it is, there seems to be overlap between PDZ-SAPs and TARPs in AMPAR maturation and cytosolic trafficking, and overlaps between GluR-Ctails and TARPs in synaptic tethering to PDZ-SAPs. The reason for these redundancies is unclear, but it could be related to the evolution of neurons in different brain structures. For example, without GluR1 (or the GluR1-Ctail), AMPARs cannot get to the dendritic surface of CA1 pyramidal neurons 59, 65; since the GluR1 subunit is not endogenously expressed in cerebellar granule neurons in vivo 112, 116-119 how then are AMPARs found in abundant quantities on the surface of these neurons? The answer appears to be stargazin - without it, cerebellar granule cells do not respond to AMPA 95, 96. Maybe AMPAR-Ctails and TARPs do have slightly redundant trafficking properties (at least in neurons that express GluR1), but this redundancy could have important consequences when it comes to neural network signaling. It has recently been proposed that AMPARs make multivalent interactions with synaptic proteins 120. Multivalency may play an key role in synaptic weight stability, and several features emerge when one considers that spatial-temporal stability is not all-or-none, particularly when it comes to influencing the synaptic steady-state number of receptors: (1) it could add stability to AMPAR-TARP-SAP complexes (has not been addressed),
three features emerge from consideration of the supramolecular assemblies that might promote multivalent interactions (Fig. 1). First, although the exact stoichiometry of TARP per AMPAR remains unclear, and may vary depending on cell type9–12, recent models of hippocampal neurons suggest the presence of either two or four units per receptor11. Hence, synaptic TARP-containing AMPAR complexes would present two or more identical PDZ domain–binding motifs from the auxiliary subunits. Second, postsynaptic MAGUKs, which are key elements of the PSD architecture13, share the same domain topology and in particular include a repeat of three clustered class I PDZ domains14,15 that provide anchoring sites for multiple binding partners13. Furthermore, the relative orientation of the ligand-binding grooves of the first two PDZ domains of PSD-95 favors accommodating multiple ligands originating from the same face, according to a NMR-derived structural model16. Functional studies in neurons indicate that the AMPAR–Stargazin complex preferentially binds to either or both of the first two PSD-95 PDZ domains4,17. Finally, the oligomerization properties of MAGUKs add another degree of complexity that allows for multivalent interactions. In particular, PSD-95α (predominant in neurons18) can form dimeric or multimeric assemblies via the N-terminal region17. Notably, this property is critical for the AMPAR’s synaptic function, as mutants that prevent oligomerization show effects on basal AMPAR currents4,17.
What would multivalency mean in the context of LTP? Perhaps this is a key property that makes endogenous LTP possible. In the Malinow model, GluR2 populates basal synapses and LTP elicits GluR1 synaptic influx; given that GluR1/2 heteromers compose over 80% of the AMPARs on the surface [1]59 text</ref>.
REFERENCES
- 1. Bristol, U.o. in Neural pathways (2014).
- 2. Rodgriguez, P.R. (ed. Tutorial, A.I.) (Sinaur Associates Inc. & Sumanas Inc, Neuroscience 4th Ed., 2008).
- 3. Czondor, K. et al. Unified quantitative model of AMPA receptor trafficking at synapses. Proc Natl Acad Sci U S A 109, 3522-7 (2012).
- 4. Malenka, R.C., Kauer, J.A., Zucker, R.S. & Nicoll, R.A. Postsynaptic calcium is sufficient for potentiation of hippocampal synaptic transmission. Science 242, 81-4 (1988).
- 5. Kandel, E. In Search of Memory: The Emergence of a New Science of Mind. Kindle: 4361-4371 (2007).
- 6. Kandel, E.R. & Spencer, W.A. Cellular neurophysiological approaches in the study of learning. Physiol Rev 48, 65-134 (1968).
- 7. Kupfermann, I., Castellucci, V., Pinsker, H. & Kandel, E. Neuronal correlates of habituation and dishabituation of the gill-withdrawal reflex in Aplysia. Science 167, 1743-5 (1970).
- 8. Carew, T.J., Pinsker, H.M. & Kandel, E.R. Long-term habituation of a defensive withdrawal reflex in aplysia. Science 175, 451-4 (1972).
- 9. Carew, T.J., Castellucci, V.F. & Kandel, E.R. An analysis of dishabituation and sensitization of the gill-withdrawal reflex in Aplysia. International Journal of Neuroscience 2, 79-98 (1971).
- 10. Brunelli, M., Castellucci, V. & Kandel, E.R. Synaptic facilitation and behavioral sensitization in Aplysia: possible role of serotonin and cyclic AMP. Science 194, 1178-81 (1976).
- 11. Pinsker, H.M., Hening, W.A., Carew, T.J. & Kandel, E.R. Long-term sensitization of a defensive withdrawal reflex in Aplysia. Science 182, 1039-1042 (1973).
- 12. Klein, M. & Kandel, E.R. Presynaptic modulation of voltage-dependent Ca2+ current: mechanism for behavioral sensitization in Aplysia californica. Proc Natl Acad Sci U S A 75, 3512-6 (1978).
- 13. Castellucci, V. & Kandel, E.R. Presynaptic facilitation as a mechanism for behavioral sensitization in Aplysia. Science 194, 1176-8 (1976).
- 14. Castellucci, V., Pinsker, H., Kupfermann, I. & Kandel, E.R. Neuronal mechanisms of habituation and dishabituation of the gill-withdrawal reflex in Aplysia. Science 167, 1745-8 (1970).
- 15. Klein, M. & Kandel, E.R. Mechanism of calcium current modulation underlying presynaptic facilitation and behavioral sensitization in Aplysia. Proc Natl Acad Sci U S A 77, 6912-6 (1980).
- 16. Klein, M., Shapiro, E. & Kandel, E.R. Synaptic plasticity and the modulation of the Ca2+ current. J Exp Biol 89, 117-57 (1980).
- 17. Shapiro, E., Castellucci, V.F. & Kandel, E.R. Presynaptic inhibition in Aplysia involves a decrease in the Ca2+ current of the presynaptic neuron. Proc Natl Acad Sci U S A 77, 1185-9 (1980).
- 18. Castellucci, V.F. et al. Intracellular injection of t he catalytic subunit of cyclic AMP-dependent protein kinase simulates facilitation of transmitter release underlying behavioral sensitization in Aplysia. Proc Natl Acad Sci U S A 77, 7492-6 (1980).
- 19. Goelet, P., Castellucci, V.F., Schacher, S. & Kandel, E.R. The long and the short of long-term memory--a molecular framework. Nature 322, 419-22 (1986).
- 20. Martin, K.C. et al. MAP kinase translocates into the nucleus of the presynaptic cell and is required for long-term facilitation in Aplysia. Neuron 18, 899-912 (1997).
- 21. Martin, K.C. et al. Synapse-specific, long-term facilitation of aplysia sensory to motor synapses: a function for local protein synthesis in memory storage. Cell 91, 927-38 (1997).
- 22. O'Keefe, J. & Nadel, L. The Hippocampus as a Cognitive Map (Oxford University Press, London, 1978).
- 23. Scoville, W.B. & Milner, B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 20, 11-21 (1957).
- 24. Granger, A.J. & Nicoll, R.A. Expression mechanisms underlying long-term potentiation: a postsynaptic view, 10 years on. Philos Trans R Soc Lond B Biol Sci 369, 20130136 (2014).
- 25. Nicoll, R.A. & Malenka, R.C. Contrasting properties of two forms of long-term potentiation in the hippocampus. Nature 377, 115-8 (1995).
- 26. Nicoll, R.A. & Schmitz, D. Synaptic plasticity at hippocampal mossy fibre synapses. Nat Rev Neurosci 6, 863-76 (2005).
- 27. Nicoll, R.A. Expression mechanisms underlying long-term potentiation: a postsynaptic view. Philos Trans R Soc Lond B Biol Sci 358, 721-6 (2003).
- 28. Malinow, R. & Malenka, R.C. AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci 25, 103-26 (2002).
- 29. Bredt, D.S. & Nicoll, R.A. AMPA receptor trafficking at excitatory synapses. Neuron 40, 361-79 (2003).
- 30. Shepherd, J.D. & Huganir, R.L. The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu. Rev. Cell Dev. Biol. 23, 613-643 (2007).
- 31. Bliss, T.V. & Collingridge, G.L. Expression of NMDA receptor-dependent LTP in the hippocampus: bridging the divide. Mol. Brain 6 (2013).
- 32. Bliss, T.V. & Lomo, T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 232, 331-56 (1973).
- 33. Racine, R.J., Milgram, N.W. & Hafner, S. Long-term potentiation phenomena in the rat limbic forebrain. Brain Res 260, 217-31 (1983).
- 34. Bliss, T.V. & Collingridge, G.L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31-9 (1993).
- 35. Malenka, R.C. & Nicoll, R.A. Long-term potentiation--a decade of progress? Science 285, 1870-4 (1999).
- 36. Nicoll, R.A. & Roche, K.W. Long-term potentiation: peeling the onion. Neuropharmacology 74, 18-22 (2013).
- 37. Dobrunz, L.E. & Stevens, C.F. Response of hippocampal synapses to natural stimulation patterns. Neuron 22, 157-66 (1999).
- 38. Otto, T., Eichenbaum, H., Wible, C.G. & Wiener, S.I. Learning‐related patterns of CA1 spike trains parallel stimulation parameters optimal for inducing hippocampal long‐term potentiation. Hippocampus 1, 181-192 (1991).
- 39. Feder, R. & Ranck, J.B., Jr. Studies on single neurons in dorsal hippocampal formation and septum in unrestrained rats. II. Hippocampal slow waves and theta cell firing during bar pressing and other behaviors. Exp Neurol 41, 532-55 (1973).
- 40. Ranck, J.B., Jr. Studies on single neurons in dorsal hippocampal formation and septum in unrestrained rats. I. Behavioral correlates and firing repertoires. Exp Neurol 41, 461-531 (1973).
- 41. Madison, D.V., Malenka, R.C. & Nicoll, R.A. Mechanisms underlying long-term potentiation of synaptic transmission. Annu Rev Neurosci 14, 379-97 (1991).
- 42. Delaney, K.R., Zucker, R.S. & Tank, D.W. Calcium in motor nerve terminals associated with posttetanic potentiation. J Neurosci 9, 3558-67 (1989).
- 43. Collingridge, G.L., Kehl, S.J. & McLennan, H.t. Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus. The Journal of Physiology 334, 33-46 (1983).
- 44. Lynch, G., Larson, J., Kelso, S., Barrionuevo, G. & Schottler, F. Intracellular injections of EGTA block induction of hippocampal long-term potentiation. Nature 305, 719-21 (1983).
- 45. Luscher, C., Nicoll, R.A., Malenka, R.C. & Muller, D. Synaptic plasticity and dynamic modulation of the postsynaptic membrane. Nat Neurosci 3, 545-50 (2000).
- 46. Song, I. & Huganir, R.L. Regulation of AMPA receptors during synaptic plasticity. Trends Neurosci 25, 578-88 (2002).
- 47. Sheng, M. & Kim, M.J. Postsynaptic signaling and plasticity mechanisms. Science 298, 776-80 (2002).
- 48. Bassani, S., Folci, A., Zapata, J. & Passafaro, M. AMPAR trafficking in synapse maturation and plasticity. Cell Mol Life Sci 70, 4411-30 (2013).
- 49. Bats, C., Groc, L. & Choquet, D. The interaction between Stargazin and PSD-95 regulates AMPA receptor surface trafficking. Neuron 53, 719-34 (2007).
- 50. Collingridge, G.L., Isaac, J.T. & Wang, Y.T. Receptor trafficking and synaptic plasticity. Nat Rev Neurosci 5, 952-62 (2004).
- 51. Makino, H. & Malinow, R. AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis. Neuron 64, 381-90 (2009).
- 52. Borgdorff, A.J. & Choquet, D. Regulation of AMPA receptor lateral movements. Nature 417, 649-53 (2002).
- 53. Yudowski, G.A. et al. Real-time imaging of discrete exocytic events mediating surface delivery of AMPA receptors. J Neurosci 27, 11112-21 (2007).
- 54. Keinanen, K. et al. A family of AMPA-selective glutamate receptors. Science 249, 556-60 (1990).
- 55. Hollmann, M., O'Shea-Greenfield, A., Rogers, S.W. & Heinemann, S. Cloning by functional expression of a member of the glutamate receptor family. Nature 342, 643-8 (1989).
- 56. Rogers, S.W. et al. The characterization and localization of the glutamate receptor subunit GluR1 in the rat brain. J Neurosci 11, 2713-24 (1991).
- 57. Black, D.L. & Grabowski, P.J. Alternative pre-mRNA splicing and neuronal function. Prog Mol Subcell Biol 31, 187-216 (2003).
- 58. Greger, I.H., Ziff, E.B. & Penn, A.C. Molecular determinants of AMPA receptor subunit assembly. Trends Neurosci 30, 407-16 (2007).
- 59. Lu, W. et al. Subunit composition of synaptic AMPA receptors revealed by a single-cell genetic approach. Neuron 62, 254-68 (2009).
- 60. Higuchi, M. et al. Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature 406, 78-81 (2000).
- 61. Bowie, D. & Mayer, M.L. Inward rectification of both AMPA and kainate subtype glutamate receptors generated by polyamine-mediated ion channel block. Neuron 15, 453-62 (1995).
- 62. Brusa, R. et al. Early-onset epilepsy and postnatal lethality associated with an editing-deficient GluR-B allele in mice. Science 270, 1677-80 (1995).
- 63. Zamanillo, D. et al. Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science 284, 1805-11 (1999).
- 64. Ehlers, M.D., Heine, M., Groc, L., Lee, M.C. & Choquet, D. Diffusional trapping of GluR1 AMPA receptors by input-specific synaptic activity. Neuron 54, 447-60 (2007).
- 65. Granger, A.J., Shi, Y., Lu, W., Cerpas, M. & Nicoll, R.A. LTP requires a reserve pool of glutamate receptors independent of subunit type. Nature 493, 495-500 (2013).
- 66. Kessels, H.W., Kopec, C.D., Klein, M.E. & Malinow, R. Roles of stargazin and phosphorylation in the control of AMPA receptor subcellular distribution. Nat Neurosci 12, 888-96 (2009).
- 67. Shi, S., Hayashi, Y., Esteban, J.A. & Malinow, R. Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell 105, 331-43 (2001).
- 68. Hayashi, Y. et al. Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 287, 2262-7 (2000).
- 69. Kornau, H.C., Schenker, L.T., Kennedy, M.B. & Seeburg, P.H. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 269, 1737-40 (1995).
- 70. Luck, K., Charbonnier, S. & Trave, G. The emerging contribution of sequence context to the specificity of protein interactions mediated by PDZ domains. FEBS Lett 586, 2648-61 (2012).
- 71. Sheng, M. & Sala, C. PDZ domains and the organization of supramolecular complexes. Annu Rev Neurosci 24, 1-29 (2001).
- 72. Xu, W. PSD-95-like membrane associated guanylate kinases (PSD-MAGUKs) and synaptic plasticity. Curr Opin Neurobiol 21, 306-12 (2011).
- 73. Zheng, C.Y., Seabold, G.K., Horak, M. & Petralia, R.S. MAGUKs, synaptic development, and synaptic plasticity. Neuroscientist 17, 493-512 (2011).
- 74. Ernst, A. et al. A structural portrait of the PDZ domain family. J Mol Biol 426, 3509-19 (2014).
- 75. Beique, J.C. et al. Synapse-specific regulation of AMPA receptor function by PSD-95. Proc Natl Acad Sci U S A 103, 19535-40 (2006).
- 76. Ehrlich, I. & Malinow, R. Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity. J Neurosci 24, 916-27 (2004).
- 77. Elias, G.M. et al. Synapse-specific and developmentally regulated targeting of AMPA receptors by a family of MAGUK scaffolding proteins. Neuron 52, 307-20 (2006).
- 78. Schluter, O.M., Xu, W. & Malenka, R.C. Alternative N-terminal domains of PSD-95 and SAP97 govern activity-dependent regulation of synaptic AMPA receptor function. Neuron 51, 99-111 (2006).
- 79. Rumbaugh, G., Sia, G.M., Garner, C.C. & Huganir, R.L. Synapse-associated protein-97 isoform-specific regulation of surface AMPA receptors and synaptic function in cultured neurons. J Neurosci 23, 4567-76 (2003).
- 80. Howard, M.A., Elias, G.M., Elias, L.A., Swat, W. & Nicoll, R.A. The role of SAP97 in synaptic glutamate receptor dynamics. Proc Natl Acad Sci U S A 107, 3805-10 (2010).
- 81. Cai, C., Coleman, S.K., Niemi, K. & Keinanen, K. Selective binding of synapse-associated protein 97 to GluR-A alpha-amino-5-hydroxy-3-methyl-4-isoxazole propionate receptor subunit is determined by a novel sequence motif. J Biol Chem 277, 31484-90 (2002).
- 82. Leonard, A.S., Davare, M.A., Horne, M.C., Garner, C.C. & Hell, J.W. SAP97 is associated with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit. J Biol Chem 273, 19518-24 (1998).
- 83. Shen, L., Liang, F., Walensky, L.D. & Huganir, R.L. Regulation of AMPA receptor GluR1 subunit surface expression by a 4. 1N-linked actin cytoskeletal association. J Neurosci 20, 7932-40 (2000).
- 84. Lin, D.T. et al. Regulation of AMPA receptor extrasynaptic insertion by 4.1N, phosphorylation and palmitoylation. Nat Neurosci 12, 879-87 (2009).
- 85. Lisman, J.E. & Zhabotinsky, A.M. A model of synaptic memory: a CaMKII/PP1 switch that potentiates transmission by organizing an AMPA receptor anchoring assembly. Neuron 31, 191-201 (2001).
- 86. Dong, H. et al. GRIP: a synaptic PDZ domain-containing protein that interacts with AMPA receptors. Nature 386, 279-84 (1997).
- 87. Dong, H. et al. Characterization of the glutamate receptor-interacting proteins GRIP1 and GRIP2. J Neurosci 19, 6930-41 (1999).
- 88. Dong, H., Zhang, P., Liao, D. & Huganir, R.L. Characterization, expression, and distribution of GRIP protein. Ann N Y Acad Sci 868, 535-40 (1999).
- 89. Srivastava, S. et al. Novel anchorage of GluR2/3 to the postsynaptic density by the AMPA receptor-binding protein ABP. Neuron 21, 581-91 (1998).
- 90. Perez, J.L. et al. PICK1 targets activated protein kinase Calpha to AMPA receptor clusters in spines of hippocampal neurons and reduces surface levels of the AMPA-type glutamate receptor subunit 2. J Neurosci 21, 5417-28 (2001).
- 91. Dakoji, S., Tomita, S., Karimzadegan, S., Nicoll, R.A. & Bredt, D.S. Interaction of transmembrane AMPA receptor regulatory proteins with multiple membrane associated guanylate kinases. Neuropharmacology 45, 849-56 (2003).
- 92. Nicoll, R.A., Tomita, S. & Bredt, D.S. Auxiliary subunits assist AMPA-type glutamate receptors. Science 311, 1253-6 (2006).
- 93. Ziff, E.B. TARPs and the AMPA receptor trafficking paradox. Neuron 53, 627-33 (2007).
- 94. Chen, L., Bao, S., Qiao, X. & Thompson, R.F. Impaired cerebellar synapse maturation in waggler, a mutant mouse with a disrupted neuronal calcium channel gamma subunit. Proc Natl Acad Sci U S A 96, 12132-7 (1999).
- 95. Hashimoto, K. et al. Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer. J Neurosci 19, 6027-36 (1999).
- 96. Osten, P. & Stern-Bach, Y. Learning from stargazin: the mouse, the phenotype and the unexpected. Current opinion in neurobiology 16, 275-280 (2006).
- 97. Chen, L. et al. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408, 936-43 (2000).
- 98. Tomita, S. et al. Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins. The Journal of cell biology 161, 805-816 (2003).
- 99. Yamazaki, M. et al. A novel action of stargazin as an enhancer of AMPA receptor activity. Neuroscience research 50, 369-374 (2004).
- 100. Nakagawa, T., Cheng, Y., Ramm, E., Sheng, M. & Walz, T. Structure and different conformational states of native AMPA receptor complexes. Nature 433, 545-549 (2005).
- 101. Moss, F.J., Dolphin, A.C. & Clare, J.J. Human neuronal stargazin-like proteins, γ2, γ3 and γ4; an investigation of their specific localization in human brain and their influence on CaV2. 1 voltage-dependent calcium channels expressed in Xenopus oocytes. BMC neuroscience 4, 23 (2003).
- 102. Rouach, N. et al. TARP γ-8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity. Nature neuroscience 8, 1525-1533 (2005).
- 103. Bedoukian, M.A., Weeks, A.M. & Partin, K.M. Different domains of the AMPA receptor direct stargazin-mediated trafficking and stargazin-mediated modulation of kinetics. Journal of Biological Chemistry 281, 23908-23921 (2006).
- 104. Vandenberghe, W., Nicoll, R.A. & Bredt, D.S. Interaction with the unfolded protein response reveals a role for stargazin in biosynthetic AMPA receptor transport. The Journal of neuroscience 25, 1095-1102 (2005).
- 105. Ayalon, G. & Stern-Bach, Y. Functional assembly of AMPA and kainate receptors is mediated by several discrete protein-protein interactions. Neuron 31, 103-113 (2001).
- 106. Ives, J.H., Fung, S., Tiwari, P., Payne, H.L. & Thompson, C.L. Microtubule-associated protein light chain 2 is a stargazin-AMPA receptor complex-interacting protein in vivo. Journal of Biological Chemistry 279, 31002-31009 (2004).
- 107. Vandenberghe, W., Nicoll, R.A. & Bredt, D.S. Stargazin is an AMPA receptor auxiliary subunit. Proceedings of the National Academy of Sciences of the United States of America 102, 485-490 (2005).
- 108. Priel, A. et al. Stargazin reduces desensitization and slows deactivation of the AMPA-type glutamate receptors. The Journal of neuroscience 25, 2682-2686 (2005).
- 109. Turetsky, D., Garringer, E. & Patneau, D.K. Stargazin modulates native AMPA receptor functional properties by two distinct mechanisms. The Journal of neuroscience 25, 7438-7448 (2005).
- 110. Tomita, S. et al. Stargazin modulates AMPA receptor gating and trafficking by distinct domains. Nature 435, 1052-1058 (2005).
- 111. Vandenberghe, W., Nicoll, R.A. & Bredt, D.S. Stargazin is an AMPA receptor auxiliary subunit. Proc Natl Acad Sci U S A 102, 485-90 (2005).
- 112. Rahmatullah, M., Ginnan, R. & Robishaw, J.D. Specificity of G Protein-Subunit Interactions N-TERMINAL 15 AMINO ACIDS OF SUBUNIT SPECIFIES INTERACTION WITH α SUBUNIT. Journal of Biological Chemistry 270, 2946-2951 (1995).
- 113. Barry, M.F. & Ziff, E.B. Receptor trafficking and the plasticity of excitatory synapses. Current opinion in neurobiology 12, 279-286 (2002).
- 114. Newpher, T.M. & Ehlers, M.D. Spine microdomains for postsynaptic signaling and plasticity. Trends Cell Biol 19, 218-27 (2009).
- 115. Rust, M.B. et al. Learning, AMPA receptor mobility and synaptic plasticity depend on n-cofilin-mediated actin dynamics. EMBO J 29, 1889-902 (2010).
- 116. Harris, K.M. Online Database. (2014).
- 117. Harris, K.M. & Weinberg, R.J. Ultrastructure of synapses in the mammalian brain. Cold Spring Harb Perspect Biol 4 (2012).
- 118. Harris, K.M. & Stevens, J.K. Dendritic spines of CA 1 pyramidal cells in the rat hippocampus: serial electron microscopy with reference to their biophysical characteristics. J Neurosci 9, 2982-97 (1989).
- 119. Bourne, J.N. & Harris, K.M. Balancing structure and function at hippocampal dendritic spines. Annu Rev Neurosci 31, 47-67 (2008).
- 120. Sheng, M. & Hoogenraad, C.C. The postsynaptic architecture of excitatory synapses: a more quantitative view. Annu Rev Biochem 76, 823-47 (2007).
- 121. Hotulainen, P. & Hoogenraad, C.C. Actin in dendritic spines: connecting dynamics to function. J Cell Biol 189, 619-29 (2010).
- 122. Grutzendler, J., Kasthuri, N. & Gan, W.B. Long-term dendritic spine stability in the adult cortex. Nature 420, 812-6 (2002).
- 123. Trachtenberg, J.T. et al. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 420, 788-94 (2002).
- 124. Roberts, T.F., Tschida, K.A., Klein, M.E. & Mooney, R. Rapid spine stabilization and synaptic enhancement at the onset of behavioural learning. Nature 463, 948-52 (2010).
- 125. Yuste, R. & Bonhoeffer, T. Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu Rev Neurosci 24, 1071-89 (2001).
- 126. Kasai, H., Matsuzaki, M., Noguchi, J., Yasumatsu, N. & Nakahara, H. Structure-stability-function relationships of dendritic spines. Trends Neurosci 26, 360-8 (2003).
- 127. Bindschadler, M. Modeling actin dynamics. Wiley Interdiscip Rev Syst Biol Med 2, 481-8 (2010).
- 128. Park, M. et al. Plasticity-induced growth of dendritic spines by exocytic trafficking from recycling endosomes. Neuron 52, 817-30 (2006).
- 129. Opazo, P. et al. CaMKII triggers the diffusional trapping of surface AMPARs through phosphorylation of stargazin. Neuron 67, 239-52 (2010).
- 130. Opazo, P., Sainlos, M. & Choquet, D. Regulation of AMPA receptor surface diffusion by PSD-95 slots. Curr Opin Neurobiol 22, 453-60 (2012).
- 131. Simon, C.M., Hepburn, I., Chen, W. & De Schutter, E. The role of dendritic spine morphology in the compartmentalization and delivery of surface receptors. J Comput Neurosci 36, 483-97 (2014).
- 132. Matsuzaki, M., Honkura, N., Ellis-Davies, G.C. & Kasai, H. Structural basis of long-term potentiation in single dendritic spines. Nature 429, 761-6 (2004).
- 133. Holcman, D. & Schuss, Z. Diffusion laws in dendritic spines. J Math Neurosci 1, 10 (2011).
- 134. Biess, A., Korkotian, E. & Holcman, D. Diffusion in a dendritic spine: the role of geometry. Phys Rev E Stat Nonlin Soft Matter Phys 76, 021922 (2007).
- 135. Shouval, H.Z. Clusters of interacting receptors can stabilize synaptic efficacies. Proc Natl Acad Sci U S A 102, 14440-5 (2005).
- 136. Tanaka, J. et al. Number and density of AMPA receptors in single synapses in immature cerebellum. J Neurosci 25, 799-807 (2005).
- 137. Matus, A. Actin-based plasticity in dendritic spines. Science 290, 754-8 (2000).
- 138. Cingolani, L.A. et al. Activity-dependent regulation of synaptic AMPA receptor composition and abundance by beta3 integrins. Neuron 58, 749-62 (2008).
- 139. Kennedy, M.B., Beale, H.C., Carlisle, H.J. & Washburn, L.R. Integration of biochemical signalling in spines. Nat Rev Neurosci 6, 423-34 (2005).
- 140. Renner, M., Specht, C.G. & Triller, A. Molecular dynamics of postsynaptic receptors and scaffold proteins. Curr Opin Neurobiol 18, 532-40 (2008).
- 141. Hoogenraad, C.C. et al. Liprinalpha1 degradation by calcium/calmodulin-dependent protein kinase II regulates LAR receptor tyrosine phosphatase distribution and dendrite development. Dev Cell 12, 587-602 (2007).
- 142. Mathworks. (Natick, Massachusetts, 2010).
- 143. Bindschadler, M., Osborn, E.A., Dewey, C.F., Jr. & McGrath, J.L. A mechanistic model of the actin cycle. Biophys J 86, 2720-39 (2004).
- 144. Yarmola, E.G., Dranishnikov, D.A. & Bubb, M.R. Effect of profilin on actin critical concentration: a theoretical analysis. Biophys J 95, 5544-73 (2008).
- 145. Mogilner, A. On the edge: modeling protrusion. Curr Opin Cell Biol 18, 32-9 (2006).
- 146. Gray, N.W., Weimer, R.M., Bureau, I. & Svoboda, K. Rapid redistribution of synaptic PSD-95 in the neocortex in vivo. PLoS Biol 4, e370 (2006).
- 147. Xu, W. et al. Molecular dissociation of the role of PSD-95 in regulating synaptic strength and LTD. Neuron 57, 248-62 (2008).
- 148. Holcman, D. & Triller, A. Modeling synaptic dynamics driven by receptor lateral diffusion. Biophys J 91, 2405-15 (2006).
- 149. Earnshaw, B.A. & Bressloff, P.C. Modeling the role of lateral membrane diffusion in AMPA receptor trafficking along a spiny dendrite. J Comput Neurosci 25, 366-89 (2008).
- 150. Jaskolski, F., Mayo-Martin, B., Jane, D. & Henley, J.M. Dynamin-dependent membrane drift recruits AMPA receptors to dendritic spines. J Biol Chem 284, 12491-503 (2009).
- 151. Holcman, D. & Schuss, Z. Control of flux by narrow passages and hidden targets in cellular biology. Rep Prog Phys 76, 074601 (2013).
- 152. Holcman, D., Hoze, N. & Schuss, Z. Narrow escape through a funnel and effective diffusion on a crowded membrane. Phys Rev E Stat Nonlin Soft Matter Phys 84, 021906 (2011).
- 153. Bourne, J.N. & Harris, K.M. Nanoscale analysis of structural synaptic plasticity. Curr Opin Neurobiol 22, 372-82 (2012).
- 154. Sorra, K.E. & Harris, K.M. Overview on the structure, composition, function, development, and plasticity of hippocampal dendritic spines. Hippocampus 10, 501-11 (2000).
- 155. Ashby, M.C., Maier, S.R., Nishimune, A. & Henley, J.M. Lateral diffusion drives constitutive exchange of AMPA receptors at dendritic spines and is regulated by spine morphology. J Neurosci 26, 7046-55 (2006).
- 156. Hoze, N. et al. Heterogeneity of AMPA receptor trafficking and molecular interactions revealed by superresolution analysis of live cell imaging. Proc Natl Acad Sci U S A 109, 17052-7 (2012).
- 157. Renner, M., Choquet, D. & Triller, A. Control of the postsynaptic membrane viscosity. J Neurosci 29, 2926-37 (2009).
Wiki References
- ↑ Cite error: Invalid
<ref>
tag; no text was provided for refs namedLu Nicoll 2009
FOOTNOTES
- [i] Expression of a protein on a null background involves using CRE to selectively excise genes that have been previously flanked by LoxP sites. In this case genes coding for GluA1-3 were removed by CRE, resulting in the complete absence of AMPARs. On this AMPAR-null background, mutant GluR can then be expressed to isolate effects limited to a single subunit. The term overexpression refers to a method where virus or biolistic transfection is used to insert an extra copy of some gene on a wild-type background (one where the endogenous gene is left intact); since there are now two (or more) copies of that gene encoding for a single type of protein, overexpressed genes often result in overexpressed proteins compared to the wild-type.
- [ii] Interestingly, despite it’s significantly reduced surface expression, GluR1ΔC rescued EPSCs to the same degree as full-length GluR1.
- [iii] Actin and MAGUKs are ancient proteins. MAGUKs are a highly conserved group of proteins that can be found in the dendritic spines of the human brain. Interestingly they are also found in single-celled organisms like choanoflagellate protists (perhaps the prehistoric organism from which metazoans evolved), and nervous system-lacking metazoans (e.g. sponges). MAGUK-containing junctional complexes evolved very early, likely for probing the environment and regulating exocytosis/endocytosis. It's thought that when metazoans evolved, these junctional complexes were co-opted for functions at neuronal synapses.
- [iv] Stargazin & γ-1 are different names for the same protein. Original this protein was designated as γ-2 based on similar sequence homology with the γ-1 L-type Ca2+ channel. Subsequently, this protein has often referred to as stargazin because it was found to be the mutated gene in stargazer mice; in fact various reviews suggest γ-1 and γ-2 share very little functional similarities. Overall, there have been 8 proteins identified in this class, while only 4 of them, γ-2,-3,-4,-8 are considered TARPs.
- [v] mEPSP or mini-EPSP are cellular responses to synaptically-released glutamate.
- [vi] Hitherto, it seemed as if the public was waiting for a study to mitigate their general dissonance on this issue, so when a TARP named stargazin was discovered to furnish this putative link, indeed a star was born.
- [vii] It should be noted that this finding was limited to COS cells, as the authors point out: ”Although we were unable to co-immunoprecipitate stargazin with GluR from brain extracts (data not shown), the harsh conditions required for solubilization of the PSD disrupt many protein complexes and often preclude detection of interactions.” (Chen, et al. 2000)
- [viii] γ-2, γ-3, γ-4, and γ-8 have all been shown to rescue mEPSCs in the stargazer mouse.
- [ix] (1) whether it has a bound nucleotide, and if so, which of three hydrolysis states [adenosine triphosphate (ATP), adenosine diphosphate (ADP), or ADP with bound inorganic phosphate (Pi)] that nucleotide is in, (2) which end of the filament it is associating with or dissociating from, (3) the state of the bound nucleotide of the existing filament end (and possibly deeper into the filament as well), (4) the age of the filament,2 (5) what binding proteins are associated with the actin monomer, (6) what binding or bundling proteins are associated with the filament, and finally (7) the magnitude of a force exerted on the filament (Bindschadler 2010).
- [x] This is in contrast to representing probabilistic forces solely as geometric fields. Probabilistic/stochastic processes can be assigned to a defined spatial region (e.g. SAP binding) without the need to render individual particles; but this convention precludes asking questions about particle turnover (e.g. what percent of the original SAP particles remain after 24 hours?). [I’m not 100% certain about the accuracy of the previous statement - it seems logical but still need to confirm with Danny or better yet Shouval or Holcman].
Pages in category "Synaptic Plasticity"
The following 11 pages are in this category, out of 11 total.
Media in category "Synaptic Plasticity"
The following 33 files are in this category, out of 33 total.
-
AMPAR Ctail PDZ.jpg 872 × 745; 432 KB
-
Bindschadler2004.png 933 × 638; 244 KB
-
Harris Tsao 1992 F7.png 769 × 625; 65 KB
-
Hoze Choquet Holcman 2012.png 289 × 616; 105 KB
-
Kusumi 2011 F1.png 403 × 223; 120 KB
-
Lu Nicoll 2009 F1.jpg 2,241 × 1,782; 282 KB
-
Lu Nicoll 2009 FIG1.jpg 2,241 × 1,782; 282 KB
-
Lu Nicoll 2009 FIG2.jpg 2,905 × 3,584; 714 KB
-
Lu Nicoll 2009 FIG3.jpg 2,905 × 3,584; 714 KB
-
Lu Nicoll 2009 FIG4.jpg 2,905 × 2,731; 594 KB
-
Lu Nicoll 2009 FIG5.jpg 2,905 × 2,775; 710 KB
-
Lu Nicoll 2009 FIG6.jpg 2,241 × 2,411; 437 KB
-
MacGillavry Blanpied 2013 Fig1.png 620 × 821; 235 KB
-
MacGillavry Blanpied 2013 Fig2.png 613 × 566; 190 KB
-
MacGillavry Blanpied 2013 Fig3.png 624 × 859; 258 KB
-
MacGillavry Blanpied 2013 Fig4ae.png 462 × 649; 96 KB
-
MacGillavry Blanpied 2013 Fig4fi.png 470 × 484; 64 KB
-
Mmc10.mov ; 1.04 MB
-
Mmc12.mov ; 2.77 MB
-
Mmc2.mov ; 2.08 MB
-
Mmc4.mov ; 2.15 MB
-
Mmc6.mov ; 2.16 MB
-
Mmc8.mov ; 1.48 MB
-
Neuron Synapse.png 1,000 × 783; 611 KB
-
Pollard2007SI1.mov ; 648 KB
-
Pollard2007SI2.mov ; 1.21 MB
-
Resolft actin.png 980 × 574; 591 KB
-
Sheng Hoogenrad 2007 Fig3.jpg 902 × 1,106; 338 KB
-
Sheng Hoogenrad 2007 Fig4.jpg 903 × 688; 119 KB
-
Sheng Hoogenrad 2007 Fig5.png 579 × 439; 318 KB
-
Sheng Kim 2005 F3.png 826 × 484; 411 KB
-
Sheng Kim 2005.png 831 × 536; 97 KB
-
Stargazin PDZ Sequence.png 511 × 589; 126 KB