Ubiquitous Plasticity and Memory Storage
2007; Cell Press; Volume: 56; Issue: 4 Linguagem: Inglês
10.1016/j.neuron.2007.10.030
ISSN1097-4199
AutoresSang Jeong Kim, David J. Linden,
Tópico(s)Advanced Memory and Neural Computing
ResumoTo date, most hypotheses of memory storage in the mammalian brain have focused upon long-term synaptic potentiation and depression (LTP and LTD) of fast glutamatergic excitatory postsynaptic currents (EPSCs). In recent years, it has become clear that many additional electrophysiological components of neurons, from electrical synapses to glutamate transporters to voltage-sensitive ion channels, can also undergo use-dependent long-term plasticity. Models of memory storage that incorporate this full range of demonstrated electrophysiological plasticity are better able to account for both the storage of memory in neuronal networks and the complexities of memory storage, indexing, and recall as measured behaviorally. To date, most hypotheses of memory storage in the mammalian brain have focused upon long-term synaptic potentiation and depression (LTP and LTD) of fast glutamatergic excitatory postsynaptic currents (EPSCs). In recent years, it has become clear that many additional electrophysiological components of neurons, from electrical synapses to glutamate transporters to voltage-sensitive ion channels, can also undergo use-dependent long-term plasticity. Models of memory storage that incorporate this full range of demonstrated electrophysiological plasticity are better able to account for both the storage of memory in neuronal networks and the complexities of memory storage, indexing, and recall as measured behaviorally. If an extraterrestrial neuroscientist managed to obtain a badge and abstract book and attend the Society for Neuroscience annual meeting, she could be forgiven for concluding that humans believe that memory storage is solely accomplished through LTP/LTD of fast (ionotropic) neurotransmission at excitatory, glutamatergic synapses. Indeed, the vast majority of presentations would support this conclusion. She might not realize that many additional aspects of glutamatergic neurotransmission can undergo LTP/LTD including slow neurotransmission (mediated by mGluRs) and glutamate reuptake. Furthermore, it might not be obvious that nonglutamatergic synapses, both chemical and electrical, express LTP/LTD. And she might be similarly surprised to learn that many of the voltage-sensitive ion channels in the dendrites and soma that underlie and modulate signal integration and spiking are similarly plastic (Figure 1). We suggest that, in time, all electrophysiological functions of neurons will be shown to undergo long-term use-dependent modulation. However, while electrophysiological plasticity is ubiquitous, not all plasticity is directly involved in constituting the memory trace, what we call mnemonic plasticity. Rather, some non-mnemonic forms of plasticity are homeostatic (Turrigiano, 1999Turrigiano G.G. Homeostatic plasticity in neuronal networks: the more things change, the more they stay the same.Trends Neurosci. 1999; 22: 221-227Abstract Full Text Full Text PDF PubMed Scopus (582) Google Scholar, Abbott and Nelson, 2000Abbott L.F. Nelson S.B. Synaptic plasticity: taming the beast.Nat. Neurosci. 2000; 3: 1178-1183Crossref PubMed Scopus (1315) Google Scholar, Desai, 2003Desai N.S. Homeostatic plasticity in the CNS: synaptic and intrinsic forms.J. Physiol. (Paris). 2003; 97: 391-402Crossref PubMed Scopus (110) Google Scholar) and thereby are permissive for memory storage in neuronal networks. Other non-mnemonic forms of electrophysiological plasticity are metaplastic (Huang et al., 1992Huang Y.Y. Colino A. Selig D.K. Malenka R.C. The influence of prior synaptic activity on the induction of long-term potentiation.Science. 1992; 255: 730-733Crossref PubMed Scopus (311) Google Scholar, Abraham and Bear, 1996Abraham W.C. Bear M.F. Metaplasticity: the plasticity of synaptic plasticity.Trends Neurosci. 1996; 19: 126-130Abstract Full Text PDF PubMed Scopus (1122) Google Scholar), impacting the probability of inducing subsequent mnemonic plasticity and thereby supporting high-order aspects of memory such as savings, blocking, or generalization. When long-term potentiation (LTP) was first reported at the glutamatergic perforant path-dentate gyrus granule cell synapse by Bliss and Lomo, 1973Bliss 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. 1973; 232: 331-356PubMed Scopus (0) Google Scholar, neuroscientists were excited, not just because LTP seemed like a useful cellular memory mechanism, but also because it was reported in the hippocampal formation, a structure known to be important in the storage of memories for facts and events (declarative memories). The dominant thought at that time, and one that persisted for many years, was that LTP, and later long-term depression (LTD, which was first described at the glutamatergic Schaffer collateral-CA1 pyramidal cell synapse of the hippocampus by Lynch et al., 1977Lynch G.S. Dunwiddie T. Gribkoff V. Heterosynaptic depression: a postsynaptic correlate of long-term potentiation.Nature. 1977; 266: 737-739Crossref PubMed Scopus (383) Google Scholar), were unusual phenomena that would only be found in the few brain regions then thought to be involved in memory storage. Now, we know that memory storage involves many additional brain regions and that LTP and LTD are widespread, having been found at glutamatergic synapses from the spinal cord to the neocortex. In the last 35 years or so, great strides have also been made in uncovering the molecular underpinnings of these phenomena and, to a lesser degree, in testing their roles in learning and memory tasks. Part of what has emerged in this process is an appreciation that LTP and LTD of fast, monosynaptic EPSCs can be triggered and expressed by a variety of different mechanisms. There are synapses where LTP and LTD are expressed presynaptically, as a change in the probability of neurotransmitter release, and others where LTP and LTD are expressed postsynaptically, as changes in the number or unitary conductance of AMPA and/or NMDA receptors in the postsynaptic density. There are many synapses where multiple forms of LTP and LTD expression occur simultaneously. Glutamate is the major excitatory neurotransmitter in the central nervous system, and fast glutamatergic EPSCs are a fundamental mode of neuronal communication. There have been many attempts to test the hypothesis that persistent, use-dependent changes in the electrical properties of neurons underlie memory storage in the brain. These tests have mostly used drugs, transfection, or mutant mice to interfere with (or occasionally to enhance) the induction and expression of LTP/LTD of fast glutamatergic EPSCs, with the hope that these manipulations would also change performance in memory tasks. While this approach has sometimes been fruitful, it has largely ignored the diversity of long-term use-dependent plasticity that electrophysiologists have uncovered in recent years. We shall give a brief overview of some of the diverse ways in which experience has been shown to produce long-term changes in the electrical function of neurons and consider whether this collection of plastic mechanisms can help us refine our models of memory storage. In so doing, we will need to define some terminology. Here, LTP and LTD will be defined by their mode of expression, not induction. So, LTP(mGluR1) indicates LTP expressed by mGluR1, not LTP triggered by mGluR1 activation and expressed as an upregulation of, say, AMPA receptors. In many synapses, bursts (but not single spikes) activate both an AMPA/NMDA receptor-mediated fast EPSC (time to peak ∼2 ms) and an mGluR1/5-mediated slow EPSC (time to peak ∼400 ms). Activation of mGluR1/5 is an important trigger of many cellular events in addition to the slow EPSC, including Ca mobilization from internal stores (via IP3 receptors) and activation of protein kinase C (PKC), MEK, and endocannabinoid signaling pathways (via phospholipase activation). Activation of mGluR1/5 is crucial for certain conventional forms of LTP and LTD expressed by AMPA receptors (Anwyl, 1999Anwyl R. Metabotropic glutamate receptors: electrophysiological properties and role in plasticity.Brain Res. Brain Res. Rev. 1999; 29: 83-120Crossref PubMed Scopus (673) Google Scholar). At a behavioral level, mGluR1/5 have been implicated in seizures (Wong et al., 1999Wong R.K. Bianchi R. Taylor G.W. Merlin L.R. Role of metabotropic glutamate receptors in epilepsy.Adv. Neurol. 1999; 79: 685-698PubMed Google Scholar), addiction (Chiamulera et al., 2001Chiamulera C. Epping-Jordan M.P. Zocchi A. Marcon C. Cottiny C. Tacconi S. Corsi M. Orzi F. Conquet F. Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice.Nat. Neurosci. 2001; 4: 873-874Crossref PubMed Scopus (475) Google Scholar), and several forms of memory storage (Riedel et al., 2003Riedel G. Platt B. Micheau J. Glutamate receptor function in learning and memory.Behav. Brain Res. 2003; 140: 1-47Crossref PubMed Scopus (711) Google Scholar) involving the hippocampus, amygdala, neocortex, striatum, and cerebellum. If mGluR1/5 activation were itself modulated, then this might have a profound metaplastic effect, changing the set point for the induction of some conventional forms of LTP and LTD. Recently, it has been shown that mGluR1 function can undergo profound use-dependent LTD (Jin et al., 2007Jin Y. Kim S.J. Kim J. Worley P.F. Linden D.J. Long-term depression of mGluR1 signaling.Neuron. 2007; 55: 277-287Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). Burst stimulation of parallel fibers releases glutamate which activates perisynaptic mGluR1 in the dendritic spines of cerebellar Purkinje cells in brain slices. The mGluR1-mediated slow EPSC activated by parallel fiber bursts was completely and persistently depressed by Ca influx triggered by strong depolarization of Purkinje cells. This depolarization-evoked depression of the slow EPSC had no effect on the fast EPSC at this same synapse which is mediated by AMPA-type glutamate receptors. LTD of the slow EPSC was also observed when slow synaptic current was evoked by exogenous application of an mGluR1-mediated agonist, implying a postsynaptic mechanism of expression. Ca imaging showed that this depression, called LTD(mGluR1), was expressed as coincident attenuation of both limbs of mGluR1 signaling: the TRPC1-medaited slow EPSC and the phospholipase C/IP3-mediated dendritic Ca mobilization. When cultured Purkinje cells were treated with an external saline supplemented with 50 mM KCl to produce strong depolarization (5 min duration), this did not trigger LTD(mGluR1), but rather resulted in an increase in surface mGluR1 immunoreactivity and a corresponding increase in the Ca transient and inward current evoked by puffs of mGluR1 agonist, LTP(mGluR1) (Minami et al., 2003Minami I. Kengaku M. Smitt P.S. Shigemoto R. Hirano T. Long-term potentiation of mGluR1 activity by depolarization-induced Homer1a in mouse cerebellar Purkinje neurons.Eur. J. Neurosci. 2003; 17: 1023-1032Crossref PubMed Scopus (44) Google Scholar). It remains to be seen if LTP(mGluR1) and LTD(mGluR1) can be expressed at the same synapses in a slice preparation and if they can reverse each other, thereby achieving bidirectional modulation. What is the function of LTD(mGluR1) and LTP(mGluR1) in Purkinje cells? One clue comes from the observation that LTD(mGluR1) blocked subsequent induction of conventional mGluR1-dependent LTD of AMPA receptors (Jin et al., 2007Jin Y. Kim S.J. Kim J. Worley P.F. Linden D.J. Long-term depression of mGluR1 signaling.Neuron. 2007; 55: 277-287Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). Thus, various forms of neuronal activity can evoke LTD of both fast ionotropic neurotransmission and/or slow mGluR1-mediated transmission at a glutamatergic synapse and the latter can have a metaplastic effect. A similar metaplastic mGluR effect may be induced in the CA1 region of the hippocampus by seizures. When chronic, recurring seizures were produced in rats following a single pilocarpine injection, this resulted in a downregulation of mGluR5 protein as assessed in hippocampal tissue using Western blots. Brain slices derived from pilocarpine-treated rats (4–10 weeks later) lacked an mGluR5-dependent form of LTD at Schaffer collateral-CA1 pyramidal cell synapses (Kirschstein et al., 2007Kirschstein T. Bauer M. Müller M. Rüschenschmidt C. Reitze M. Becker A.J. Schoch S. Beck H. Loss of metabotropic glutamate receptor-dependent long-term depression via downregulation of mGluR5 after status epilepticus.J. Neurosci. 2007; 27: 7696-7704Crossref PubMed Scopus (49) Google Scholar). The cerebellar climbing fiber-Purkinje cell synapse is an advantageous model system for the study of neuronal glutamate transporter currents. Most Purkinje cells are innervated by a single climbing fiber axon, which ramifies to form ∼1500 release sites. Each of these sites appears to release multiple vesicles of glutamate with each action potential invasion (Wadiche and Jahr, 2001Wadiche J.I. Jahr C.E. Multivesicular release at climbing fiber-Purkinje cell synapses.Neuron. 2001; 32: 301-313Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar). A single shock delivered to the climbing fiber axon results in the activation of AMPA and kainate receptors (Huang et al., 2004Huang Y.H. Dykes-Hoberg M. Tanaka K. Rothstein J.D. Bergles D.E. Climbing fiber activation of EAAT4 transporters and kainate receptors in cerebellar Purkinje cells.J. Neurosci. 2004; 24: 103-111Crossref PubMed Scopus (86) Google Scholar), and when these receptors are blocked with drugs, a synaptic glutamate transporter current is revealed. This current is mediated by the transporter EAAT4 (Huang et al., 2004Huang Y.H. Dykes-Hoberg M. Tanaka K. Rothstein J.D. Bergles D.E. Climbing fiber activation of EAAT4 transporters and kainate receptors in cerebellar Purkinje cells.J. Neurosci. 2004; 24: 103-111Crossref PubMed Scopus (86) Google Scholar), which is strongly expressed in the perisynaptic membranes of climbing fiber-Purkinje cell synapses. Tetanic stimulation of climbing fiber-Purkinje cell synapses resulted in LTP of climbing fiber-evoked EAAT4 current (Shen and Linden, 2005Shen Y. Linden D.J. Long-term potentiation of neuronal glutamate transporters.Neuron. 2005; 46: 715-722Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). This LTP(EAAT4) required activation of an mGluR1/PKC cascade and an LTP(EAAT4)-like effect produced by exogenous PKC activators could be observed using glutamate uncaging test pulses in place of climbing fiber volleys, indicating a postsynaptic locus of expression. In cerebellar Purkinje cells, blockade of glial and neuronal EAATs with the drug TBOA, produced a large increase in mGluR1 activation, presumably by increasing the amplitude of the glutamate transients at perisynaptic mGluR1 receptors. Brasnjo and Otis, 2001Brasnjo G. Otis T.S. Neuronal glutamate transporters control activation of postsynaptic metabotropic glutamate receptors and influence cerebellar long-term depression.Neuron. 2001; 31: 607-616Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar showed that this manipulation could reduce the threshold for induction of mGluR1-dependent LTD of AMPA receptors at the parallel fiber-Purkinje cell synapse. It will be interesting to determine whether LTP(EAAT4) will produce the converse effect: raising the threshold for conventional cerebellar LTD of AMPA receptors. At present, the vast majority of studies examining the synaptic substrates of memory storage have involved LTP/LTD of excitatory glutamatergic synapses. Although inhibitory synapses are widespread and crucial to nervous system function, long-term alterations of these synapses have received much less attention. Inhibitory synapses exert powerful control over synaptically-driven neuronal firing. In part, this control derives from the spatial distribution of excitatory versus inhibitory synapses. Inhibitory synapses are often found on the soma, proximal dendrites, and axon initial segment of a target neuron, whereas excitatory synapses are more likely to be found on the distal dendrites. This interposed configuration allows a single proximal inhibitory synapse to negate hundreds of integrated EPSPs by a shunting conductance and thereby influence spike frequency and timing. In a number of brain regions, including neocortex, hippocampus, and cerebellum, strong depolarization of postsynaptic neurons can give rise to LTP or LTD of GABAergic IPSCs (Gaiarsa et al., 2002Gaiarsa J.L. Caillard O. Ben-Ari Y. Long-term plasticity at GABAergic and glycinergic synapses: mechanisms and functional significance.Trends Neurosci. 2002; 25: 564-570Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar). One well-established example involves the synapses between molecular layer interneurons and cerebellar Purkinje cells, where strong postsynaptic depolarization give rise to LTP(GABA) (Kano et al., 1992Kano M. Rexhausen U. Dreessen J. Konnerth A. Synaptic excitation produces a long-lasting rebound potentiation of inhibitory synaptic signals in cerebellar Purkinje cells.Nature. 1992; 356: 601-604Crossref PubMed Scopus (292) Google Scholar) through a postsynaptic signaling cascade involving Ca influx and CaMKII (Kano et al., 1996Kano M. Kano M. Fukunaga K. Konnerth A. Ca2+-induced rebound potentiation of gamma-aminobutyric acid-mediated currents requires activation of Ca2+/calmodulin-dependent kinase II.Proc. Natl. Acad. Sci. USA. 1996; 93: 13351-13356Crossref PubMed Scopus (99) Google Scholar). At the GABAergic synapses between cerebellar Purkinje cells and the neurons of the deep cerebellar nuclei, either LTD(GABA) (Morishita and Sastry, 1996Morishita W. Sastry B.R. Postsynaptic mechanisms underlying long-term depression of GABAergic transmission in neurons of the deep cerebellar nuclei.J. Neurophysiol. 1996; 76: 59-68PubMed Google Scholar) or LTP(GABA) may be induced, depending upon the degree of postsynaptic activation (Aizenman et al., 1998Aizenman C. Manis P.B. Linden D.J. Polarity of long-term synaptic gain change is related to postsynaptic spike firing at a cerebellar inhibitory synapse.Neuron. 1998; 21: 827-835Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). In the neocortex, cell-pair recordings of synapses between fast spiking interneurons and pyramidal cells have shown that LTP(GABA) or LTD(GABA) can be induced in a spike timing-dependent fashion: LTD(GABA) in induced by near-coincident pre- and postsynaptic firing while LTP(GABA) is induced by greater temporal mismatch (Holmgren and Zilberter, 2001Holmgren C.D. Zilberter Y. Coincident spiking activity induces long-term changes in inhibition of neocortical pyramidal cells.J. Neurosci. 2001; 21: 8270-8277PubMed Google Scholar). A separate study examined LTP(GABA) in inhibitory synapses from fast-spiking basket cells to star pyramidal neurons in layer 4 of primary visual cortex (Maffei et al., 2006Maffei A. Nataraj K. Nelson S.B. Turrigiano G.G. Potentiation of cortical inhibition by visual deprivation.Nature. 2006; 443: 81-84Crossref PubMed Scopus (281) Google Scholar). LTP(GABA) could be induced by pairing of fast-spiking basket cell firing with subthreshold depolarization of star pyramidal neurons. In this case, correlated presynaptic and postsynaptic firing prevented LTP(GABA). In the ventral tegmental area, stimulation of dopaminergic neurons can evoke dendritic dopamine release and consequent activation of D2 receptors at dendrodendritic synapses. These D2 receptors activate a GIRK conductance via Gi/o proteins, resulting in a slow IPSC (time to peak ∼300 ms; Beckstead et al., 2004Beckstead M.J. Grandy M.K. Wickman K. Williams J.T. Vesicular dopamine release elicits an inhibitory postsynaptic current in midbrain dopamine neurons.Neuron. 2004; 42: 939-946Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar). Following low-frequency conditioning stimulation, LTD of the slow dopamine IPSC was observed that is likely mediated by desensitization of postsynaptic D2 receptors (Beckstead and Williams, 2007Beckstead M.J. Williams J.T. Long-term depression of a dopamine IPSC.J. Neurosci. 2007; 27: 2074-2080Crossref PubMed Scopus (48) Google Scholar). Thus, LTD has now been observed at both slow metabotropic (dopamine) and fast ionotropic (GABA-A) inhibitory synapses, further expanding the repertoire of use-dependent plasticity. It has become clear that there are large groups of neighboring inhibitory neurons that are electrically connected by gap junctions in both the neocortex and the thalamus. These connections promote synchronized firing of inhibitory networks. One such location where this occurs is the thalamic reticular nucleus, where the probability of electrical coupling between adjacent inhibitory neurons is ∼50%. These neurons also receive powerful glutamatergic drive from the neocortex that is received by synapses bearing postsynaptic mGluR1/5. Landisman and Connors, 2005Landisman C.E. Connors B.W. Long-term modulation of electrical synapses in the mammalian thalamus.Science. 2005; 310: 1809-1813Crossref PubMed Scopus (122) Google Scholar performed dual whole-cell recordings from adjacent inhibitory neurons in this structure and measured the strength of electrical synapses (by passing a hyperpolarizing current step into one cell while recording from its neighbor). They found that the strength of electrical coupling was consistent when monitoring with low-frequency test pulses for >20 min. However, when conditioning stimulation, consisting of brief bursts applied to glutamatergic synapses, was delivered, this produced an attenuation of the electrical synapses that resulted in an ∼25% depression of the coupling coefficient and which lasted for the duration of the recording (Figure 2). This LTD(electrical) could be blocked by an mGluR1/5 antagonist and mimicked by an agonist. Importantly, induction of LTD(electrical) was accompanied by a reduction in the correlation coefficient of spike firing between the two cells. It remains to be seen whether the converse phenomenon, LTP(electrical), will be found in the mammalian brain. This seems likely, given that LTP(electrical) has been previously reported at mixed electrical/chemical club ending synapses on goldfish Mauthner cells (Yang et al., 1990Yang X.D. Korn H. Faber D.S. Long-term potentiation of electrotonic coupling at mixed synapses.Nature. 1990; 348: 542-545Crossref PubMed Scopus (138) Google Scholar; see Pereda et al., 2004Pereda A.E. Rash J.E. Nagy J.I. Bennett M.V. Dynamics of electrical transmission at club endings on the Mauthner cells.Brain Res. Brain Res. Rev. 2004; 47: 227-244Crossref PubMed Scopus (92) Google Scholar, for review). (A) Infrared DIC images showing the recording configuration. Simultaneous recordings were made from a pair of electrically coupled neurons in the thalamic reticular nucleus (TRN1 and 2). A stimulating electrode was placed to activate corticothalamic fibers running in the internal capsule (IC). Scale bars indicate 1 mm and 20 μm (inset). (B) Large hyperpolarizing current injections into TRN1 evoked electrical coupling responses in TRN2. This constituted the test stimulation. Conditioning stimulation involved tetanic activation of corticothalamic fibers, which impinged upon both TRN1 and TRN2. Following conditioning stimulation, LTD(electrical) was observed. (C) A time course graph shows LTD(electrical) as a persistent decrease in coupling coefficient. From Landisman and Connors, 2005Landisman C.E. Connors B.W. Long-term modulation of electrical synapses in the mammalian thalamus.Science. 2005; 310: 1809-1813Crossref PubMed Scopus (122) Google Scholar. Reprinted with permission of AAAS. In recent years, a number of reports have demonstrated that patterns of brief synaptic stimulation, particularly bursts, can give rise to persistent changes in postsynaptic voltage-sensitive ion channel function (see Zhang and Linden, 2003Zhang W. Linden D.J. The other side of the engram: experience-dependent changes in neuronal intrinsic excitability.Nat. Rev. Neurosci. 2003; 4: 885-900Crossref PubMed Scopus (590) Google Scholar, Frick and Johnston, 2005Frick A. Johnston D. Plasticity of dendritic excitability.J. Neurobiol. 2005; 64: 100-115Crossref PubMed Scopus (108) Google Scholar, for review). One nice example comes from the sensorimotor neocortex, in which high-frequency stimulation of glutamatergic fibers from layer II/III produced a persistent increase in the intrinsic excitability of layer V pyramidal cells. This phenomenon required activation of mGluR5 and produced an increase in the number of spikes recorded in response to a constant injection of depolarizing current in the soma (Sourdet et al., 2003Sourdet V. Russier M. Daoudal G. Ankri N. Debanne D. Long-term enhancement of neuronal excitability and temporal fidelity mediated by metabotropic glutamate receptor subtype 5.J. Neurosci. 2003; 23: 10238-10248PubMed Google Scholar). It was also manifest as a reduction in the medium-duration after hyperpolarization that followed a spike burst, produced in part by the action of SK-type Ca-sensitive K channels. Many other examples of synaptically evoked changes in intrinsic excitability have been reported and they have involved a number of different induction mechanisms (NMDA receptor activation, Ca influx via voltage-gated channels) and expression mechanisms (various Na, K, Cl, and Ca conductances have all been altered). Almost all of the studies that have examined intrinsic plasticity have relied upon somatic recording, which reflects conductances in the soma, proximal axon, and the dendrites (with the proximal dendrites contributing most of the dendritic signal). One limitation of this recording mode is that it does not pinpoint the location of the plastic ion channels. If a group of K channels near the site of synaptic activation in the dendrite were modulated, this could not be distinguished from a smaller but more widespread effect on K channels. In a seminal report, Frick et al., 2004Frick A. Magee J. Johnston D. LTP is accompanied by an enhanced local excitability of pyramidal neuron dendrites.Nat. Neurosci. 2004; 7: 126-135Crossref PubMed Scopus (340) Google Scholar combined patch-clamp recording from dendrites with Ca imaging to address this question. They stimulated a group of Schaffer collateral synapses that impinged upon the distal dendrite of a hippocampal CA1 pyramidal cell. This stimulation produced conventional NMDA receptor-dependent LTP of AMPA receptors, but it also produced a local enhancement of excitability in an ∼100 μm long segment of distal dendrite (Figure 3). This was mediated in part by a hyperpolarizing shift in the steady-state inactivation of the K conductance IA measured in distal dendrite. This intrinsic plasticity was also seen as an accompanying local increase in the amplitude of single back-propagating spikes and their associated Ca transients. This result is important because it shows that local, persistent changes in a dendritic voltage-sensitive conductance can be evoked in a use-dependent manner. It opens the door to the possibility that these localized changes can constitute a portion of memory traces by modulating dendritic integration in a subset of the synaptic array. In addition, it points out that there may be units of integration in the dendrite that are intermediate between the single synapse (as modulated by conventional LTP/LTD) and the entire neuron (as modulated by intrinsic changes of axo-somatic conductances that would affect throughput from all synapses). Interestingly, it appears as if the same pattern of stimulation can produce both local and global changes in dendritic intrinsic conductances. For example, theta burst pairing can produce both the local increases in intrinsic excitability mediated by IA, as discussed previously (Frick et al., 2004Frick A. Magee J. Johnston D. LTP is accompanied by an enhanced local excitability of pyramidal neuron dendrites.Nat. Neurosci. 2004; 7: 126-135Crossref PubMed Scopus (340) Google Scholar), and a superimposed decrease in dendritic excitability that is spread across the dendritic arbor and mediated by an upregulation of a different conductance, Ih (Fan et al., 2005Fan Y. Fricker D. Brager D.H. Chen X. Lu H.C. Chitwood R.A. Johnston D. Activity-dependent decrease of excitability in rat hippocampal neurons through increases in I(h).Nat. Neurosci. 2005; 8: 1542-1551Crossref PubMed Scopus (283) Google Scholar). In the beginning (1973, actually), there was LTP of fast glutamatergic EPSPs (Bliss and Lomo, 1973Bliss 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. 1973; 232: 331-356PubMed Scopus (0) Google Scholar). Interestingly, even in the original report of LTP, it was also noted that at least one additional form of plasticity was present. The increase in population spike was greater than could be accounted for by the increase in the population EPSP caused by LTP. In fact, in some cases, population spike potentiation occurred in the absence of potentiation of the population EPSP. This phenomenon was termed the "nonsynaptic component of LTP" and later came to be known as EPSP-spike or E-S potentiation. Amazingly, the mechanism underlying E-S potentiation is still controversial with some investigators, suggesting that E-S potentiation is due to an increase in the ratio of excitatory to feed-forward inhibitory drive while others implicate an increase in the intrinsic excitability of the postsynaptic neuron (see Zhang and Linden, 2003Zhang W. Linden D.J. The other side of the engram: experience-dependent changes in neuronal intrinsic excitability.Nat. Rev. Neurosci. 2003; 4: 885
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