Long-term Depression Of Synaptic Transmission Research Articles

Presynaptic long-term depression at a central glutamatergic synapse: a role for CaMKII.

CaMKII is a calcium-activated kinase that is abundant in neurons and has been strongly implicated in memory and learning. Here we show that low-frequency stimulation of glutamatergic afferents in hippocampal slices from juvenile domestic chicks results in long-term depression of synaptic transmission. This reduction does not require activation of NMDA or metabotropic glutamate receptors and does not require a rise in postsynaptic calcium. However, buffering presynaptic calcium prevents the reduction of the excitatory postsynaptic potential or current that is induced by low-frequency stimulation. In addition, application of the calmodulin antagonist calmidazolium, or the specific CaMKII antagonist KN-93, completely blocks long-term depression. These findings demonstrate a newly discovered form of long-term synaptic depression in the avian hippocampus.

Long-term depression of synaptic transmission in the cerebellum: cellular and molecular mechanisms revisited

Long-term depression (LTD) of synaptic transmission at parallel fiber (PF)–Purkinje cell (PC) synapses in the cerebellum has been the first established example of enduring decrease of synaptic efficacy in the central nervous system. This review focuses on the underlying cellular and molecular mechanisms. Thus, at the level of the postsynaptic membranes of PCs, induction of LTD requires concomitent activation of voltage-gated calcium channels (VGCCs) and of ionotropic and metabotopic glutamate receptors, of the α-amino-3 hydroxy-5-methyl-isoxalone-4-propionate (AMPA) and mGluR1 α types respectively. Subsequent intracellular cascades involve production of nitric oxide from arginine and of cGMP, activation of phospholipase A 2 and of several protein kinases including protein kinase C and tyrosine kinases. Activation of protein kinase G and of phosphatases are also likely to be involved in LTD induction. In contrast, there are still uncertainties concerning a major role of release of calcium from internal stores in LTD induction. Finally protein synthesis is required for a late phase of LTD to occur. All available experimental evidence points towards a postsynaptic site for LTD expression. In particular, electrophysiological data demonstrate a genuine modification of the functional properties of AMPA receptors of PCs during LTD, and immunocytochemical evidence suggests that this might result from a phosphorylation of these receptors.

Secreted form of beta-amyloid precursor protein shifts the frequency dependency for induction of LTD, and enhances LTP in hippocampal slices.

The secreted form of beta-amyloid precursor protein (sAPP alpha) is released from neurons in an activity-dependent manner, and has been reported to modulate neuronal excitability in dissociated hippocampal neurons. We now report that sAPP alpha shifts the frequency dependence for induction of long-term depression of synaptic transmission (LTD) in hippocampal slices from adult rats. Whereas low frequency stimulation (1 Hz) of Schaffer collateral axons induced LTD of the post-synaptic response of CA1 neurons in control slices, it did not induce LTD in slices pretreated with sAPP alpha. On the other hand, whereas a 10 Hz stimulation normally induced neither LTD or LTP, it did induce LTD in slices pretreated with sAPP alpha. sAPP alpha potentiated LTP induced by high frequency stimulation. sAPP alpha induced cGMP production in hippocampal slices, and pretreatment of slices with 8-bromo-cyclic GMP mimicked the effect of sAPP alpha on LTD suggesting a role for cyclic GMP in modulation of LTD. The data suggest an important role for sAPP alpha in modulation of synaptic plasticity in the hippocampus.

Low-frequency stimulation induces homosynaptic depotentiation but not long-term depression of synaptic transmission in the adult anaesthetized and awake rat hippocampus in vivo

The induction of homosynaptic long-term depression and depotentiation of previously established long-term potentiation was investigated in the CA1 hippocampal region of anaesthetized and awake adult rats following prolonged ipsilateral low-frequency stimulation of the Schaffer collateral/commissural pathway. Prolonged low-frequency stimulation at 1–10 Hz failed to induce long-term depression of field excitatory postsynaptic potentials in the anaesthetized or awake adult rat. However, prolonged low-frequency stimulation at 5 and 10 Hz, although not at 1 or 2 Hz, did induce depotentiation of previously established long-term potentiation in anaesthetized animals. Thus, in the anaesthetized animals, 900 pulses at 10 Hz induced a depotentiation of 68%, 59% and 66% when given 10, 30 and 40 min following long-term potentiation induction. Depotentiation could also be induced at much longer times following the induction of long-term potentiation. Thus, in anaesthetized rats, depotentiation measuring 34% was induced by 10-Hz stimulation 4 h following long-term potentiation induction, and depotentiation measuring 60% was induced in two sets of experiments 24 h after long-term potentiation induction in awake animals. The results of the present study show that homosynaptic long-term depression was not induced in the adult hippocampus in vivo using stimulation protocols which are effective in hippocampal slices. However, erasure of long-term potentiation by the process of depotentiation has been shown to occur in the adult hippocampus in vivo, both at short times and at prolonged times after the induction of long-term potentiation.

Cellular mechanisms of long-term depression in the cerebellum

Long-term depression (LTD) of synaptic transmission at parallel fibre-Purkinje cell synapses is thought to be a cellular substrate of motor learning in the cerebellum. This use-dependent change in synaptic efficacy is induced by conjunctive stimulation of Parallel fibres and climbing fibres. Researchers agree that the induction of LTD requires, as an initial step, a calcium influx via voltage-gated Ca2+ channels into a Purkinje cell, together with activation of ionotropic (AMPA) and probably metabotropic subtypes of glutamate receptors of this cell. Indeed, due to the lack of specific antagonist, the final demonstration of the contribution of metabotropic receptors in the LTD induction process, under functional conditions, remains unanswered. The debate is now focused on the second-messenger processes leading to LTD of synaptic transmission at parallel fibre-Purkinje cell synapses, after the calcium influx into the cell. All researchers agree that a calcium-dependent cascade of events including activation of protein kinase C is necessary for LTD induction. In contrast, the recruitment in the LTD induction of another cascade, also triggered by Ca2+, that is, through synthesis of nitric oxide and cyclic GMP, remains controversial.On the other hand, growing evidence suggests that these chains of reaction underlying LTD might ultimately lead to a genuine change in the functional characteristics of AMPA receptors at the parallel fibre-Purkinje cell synapses.

Long-term modifications of synaptic efficacy in the human inferior and middle temporal cortex.

The primate temporal cortex has been demonstrated to play an important role in visual memory and pattern recognition. It is of particular interest to investigate whether activity-dependent modification of synaptic efficacy, a presumptive mechanism for learning and memory, is present in this cortical region. Here we address this issue by examining the induction of synaptic plasticity in surgically resected human inferior and middle temporal cortex. The results show that synaptic strength in the human temporal cortex could undergo bidirectional modifications, depending on the pattern of conditioning stimulation. High frequency stimulation (100 or 40 Hz) in layer IV induced long-term potentiation (LTP) of both intracellular excitatory postsynaptic potentials and evoked field potentials in layers II/III. The LTP induced by 100 Hz tetanus was blocked by 50-100 microM DL-2-amino-5-phosphonovaleric acid, suggesting that N-methyl-D-aspartate receptors were responsible for its induction. Long-term depression (LTD) was elicited by prolonged low frequency stimulation (1 Hz, 15 min). It was reduced, but not completely blocked, by DL-2-amino-5-phosphonovaleric acid, implying that some other mechanisms in addition to N-methyl-DL-aspartate receptors were involved in LTD induction. LTD was input-specific, i.e., low frequency stimulation of one pathway produced LTD of synaptic transmission in that pathway only. Finally, the LTP and LTD could reverse each other, suggesting that they can act cooperatively to modify the functional state of cortical network. These results suggest that LTP and LTD are possible mechanisms for the visual memory and pattern recognition functions performed in the human temporal cortex.

Ocular dominance plasticity under metabotropic glutamate receptor blockade.

Occluding vision through one eye during a critical period in early life nearly abolishes responses to that eye in visual cortex. This phenomenon is mimicked by long-term depression of synaptic transmission in vitro, which may require metabotropic glutamate receptors (mGluRs) and is age-dependent. Peaks in mGluR expression and glutamate-stimulated phosphoinositide turnover during visual cortical development have been proposed as biochemical bases for the critical period. Pharmacological blockade of mGluRs specifically prevented synapse weakening in mouse visual cortical slices but did not alter kitten ocular dominance plasticity in vivo. Thus, a heightened mGluR response does not account for the critical period in development.

Long-term depression of synaptic transmission induced by group in metabotropic glutamate receptor activation in the CA1 of young rat hippocampus

Long-term depression of synaptic transmission induced by group in metabotropic glutamate receptor activation in the CA1 of young rat hippocampus

Long-term depression of synaptic transmission in the adult rat hippocampus and perirhinal cortex

Long-term depression of synaptic transmission in the adult rat hippocampus and perirhinal cortex

Activation of dopamine D1 receptors enhances long-term depression of synaptic transmission induced by low frequency stimulation in rat hippocampal CA1 neurons

The effects of both activation and blockade of dopamine (DA) D1 receptors on long-term depression (LTD) of synaptic transmission were examined in CA1 neurons of rat hippocampal slices. Low frequency stimulation (LFS) consisting of 450 pulses at 1 Hz induced LTD (−14.3%, mean, n = 10) in the slope of the field excitatory postsynaptic potential. SKF-38393 (3–10 μM), an agonist of DA D1 receptors, significantly enhanced LFS-induced LTD (−31.1%, n = 11). SCH-23390 (2 μM), an antagonist of DA D1 receptors, blocked the induction of LTD by LFS (2.5%, n = 6). These results indicate that DA D1 receptors play an important role in the modulation of LFS-induced LTD in rat hippocampal CA1 neurons.

CGMP acts within cerebellar Purkinje cells to produce long term depression via mechanisms involving PKC and PKG.

Long term depression (LTD) of parallel fibre-Purkinje cell responses may result from desensitization of AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) type glutamate receptors, for which a cascade of reactions involving calcium, inositol-1,4,5-trisphosphate, nitric oxide (NO), guanosine-3'5'-monophosphate (cGMP) and protein kinases C and G has been previously proposed. The involvement of cGMP in synaptic LTD was confirmed by direct injection of cGMP and 8-bromo-cGMP (8-Br-cGMP) into the dendrites of Purkinje cells. Pairing injections with parallel fibre stimulation led to a LTD of synaptic transmission which both occluded and was occluded by heterosynaptically induced LTD. Inhibition of either protein kinases C or G prevented induction of both forms of LTD.

Metabotropic glutamate receptors contribute to the induction of long-term depression in the CA1 region of the hippocampus

Long-term depression of synaptic transmission was induced following the prior induction of long-term potentiation in the CA1 region of rat hippocampal slices. We show that the induction of this form of synaptic depression can be prevented by (+)-α-methyl-4-carboxyphenylglycine, a selective antagonist of metabotropic glutamate receptors.

Tetanization during GABA A receptor activation induces long-term depression in visual cortex slices

In rat visual cortex slices, long-term depression of synaptic transmission was induced by tetanic stimulation to white matter during bath-application of the GABA A agonist muscimol. This result supports the view that a combination of presynaptic activity and postsynaptic inhibition leads to a depression of synaptic efficiency.

Coactivation of D 1 and D 2 dopamine receptors is required for long-term synaptic depression in the striatum

Long-term changes of synaptic transmission following brief trains of high-frequency stimulation of excitatory pathways in the brain have attracted attention as a possible correlate of memory. In the cerebellum, concurrent activation of parallel fibers and climbing fibers leads to a long-term depression (LTD) of synaptic transmission, which may be the cellular substrate of motor learning in this structure. We report here for the first time that high-frequency stimulation of corticostriatal glutamatergic fibers in the striatum, another brain structure strongly involved in motor control, also induces LTD of synaptic transmission. Induction of striatal LTD is blocked either by SCH 23390, a D 1 dopamine (DA) receptor antagonist or by l-sulpiride, a D 2 DA receptor antagonist. The lesion of the nigrostriatal DAergic pathway abolishes LTD. After DA depletion, LTD can be restored by the application of exogenous DA. LTD can also be restored by coadministration of D 1 and D 2 DA receptor agonists, but not by the application of a single class of DA agonists alone. Our data show that coactivation of D 1 and D 2 DA receptors is required for LTD in the striatum. D 1/D 2 receptor cooperation in the induction of LTD may play a crucial role in the behavioural function of DA and in the therapeutic effects of DA agonists in Parkinson's disease.

Pairing of pre‐ and postsynaptic activities in cerebellar Purkinje cells induces long‐term changes in synaptic efficacy in vitro.

1. An in vitro slice preparation of rat cerebellar cortex was used to analyse long-lasting modifications of synaptic transmission at parallel fibre (PF)-Purkinje cell (PC) synapses. These use-dependent changes were induced by pairing PF-mediated EPSPs evoked at low frequency (1 Hz) with different levels of membrane polarization (or bioelectrical activities) of PCs for 15 min. 2. Experiments were performed on forty-eight PCs recorded intracellularly in a conventional perfused chamber, and in fifty other cells maintained in a static chamber either in the presence (n = 21) or in the absence (n = 29) of 400 nM-phorbol 12,13-dibutyrate (PDBu). 3. In these three experimental conditions, PF-mediated EPSPs were always measured on PCs maintained at a holding potential of -75 mV, and further hyperpolarized by constant hyperpolarizing pulses. This allowed us both to test the input resistance of PCs and to avoid their firing during PF-mediated EPSPs. 4. In all cells retained for the present study, latencies of PF-mediated EPSPs evoked at 0.2 Hz were stable during the pre-pairing period, and the same was true for their amplitude and time course. 5. In the perfused chamber, pairing of PF-mediated EPSPs with the same hyperpolarization of PCs as that used for measurements of synaptic responses had no effect on these EPSPs in 30% of PCs. It induced long-term depression (LTD) and long-term potentiation (LTP) in 23 and 47% of the tested cells respectively (n = 17). 6. In the perfused chamber, pairing of PF-mediated EPSPs with moderate depolarization of PCs (n = 19) giving rise to a sustained firing of sodium spikes significantly favoured the appearance of LTP as compared to the previous pairing protocol. However, there were still 27 and 15% of cells which showed no modification and LTD respectively. 7. In contrast, pairing of PF-mediated EPSPs with calcium (Ca2+) spikes evoked by strong depolarization of PCs (n = 12) led to LTD of synaptic transmission in nearly half of the tested cells, whereas LTP was now observed in less than 20% of them. 8. In the static chamber and in the absence of PDBu, LTD of PF-mediated EPSPs was observed in most cells, whatever the pairing protocol with sodium or Ca2+ spikes. 9. This shift towards LTD was significantly reversed by PDBu in the pairing protocol using firing of sodium spikes, but not in the case of pairings with Ca2+ spikes.(ABSTRACT TRUNCATED AT 400 WORDS)