NMDA receptor-dependent metaplasticity at hippocampal mossy fiber synapses

Hippocampal mossy fiber synapses have been reported to lack NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) of AMPA excitatory postsynaptic currents (EPSCs), unlike conventional glutamatergic synapses. An explanation for this difference may reside in the relatively low number of NMDARs at these synapses. Because mossy fiber synapses display LTP selective for NMDARs, we examined whether this would affect the plasticity rules at mossy fiber-CA3 synapses in mouse hippocampal slices. We found that LTP of NMDARs serves as a metaplastic switch making mossy fiber synapses competent for generating NMDAR-dependent LTP of AMPA EPSCs.     

Multiple forms of LTP in hippocampal CA3 neurons use a common postsynaptic mechanism.

We investigated long-term potentiation (LTP) at mossy fiber synapses on CA3 pyramidal neurons in the hippocampus. Using Ca2+ imaging techniques, we show here that when postsynaptic Ca2+ was sufficiently buffered so that [Ca2+]i did not rise during synaptic stimulation, the induction of mossy fiber LTP was prevented. In addition, induction of mossy fiber LTP was suppressed by postsynaptic injection of a peptide inhibitor of cAMP-dependent protein kinase. Finally, when ionotropic glutamate receptors were blocked, LTP depended on the postsynaptic release of Ca2+ from internal stores triggered by activation of metabotropic glutamate receptors. These results support the conclusion that mossy fiber LTP and LTP at other hippocampal synapses share a common induction mechanism involving an initial rise in postsynaptic [Ca2+].     

Mossy fiber long-term potentiation shows specificity but no apparent cooperativity.

Specificity in long-term potentiation (LTP) means that synapses onto a postsynaptic cell can potentiate independently of one another. Cooperativity refers to a requirement that some threshold number of afferents be co-activated to evoke LTP with a high-frequency stimulus. The induction of long-term potentiation (LTP) at the associational/commissural synapses onto hippocampal CA3 pyramidal cells shows clear cooperativity. LTP of mossy fiber inputs to these cells does not. Mossy fiber LTP does show synapse specificity. These results bear on the cellular mechanisms and the functions of mossy fiber LTP.     

Photolysis of postsynaptic caged Ca2+ can potentiate and depress mossy fiber synaptic responses in rat hippocampal CA3 pyramidal neurons

The induction of mossy fiber-CA3 long-term potentiation (LTP) and depression (LTD) has been variously described as being dependent on either pre- or postsynaptic factors. Some of the postsynaptic factors for LTP induction include ephrin-B receptor tyrosine kinases and a rise in postsynaptic Ca2+ ([Ca2+]i). Ca2+ is also believed to be involved in the induction of the various forms of LTD at this synapse. We used photolysis of caged Ca2+ compounds to test whether a postsynaptic rise in [Ca2+]i is sufficient to induce changes in synaptic transmission at mossy fiber synapses onto rat hippocampal CA3 pyramidal neurons. We were able to elevate postsynaptic [Ca2+]i to approximately 1 microm for a few seconds in pyramidal cell somata and dendrites. We estimate that CA3 pyramidal neurons have approximately fivefold greater endogenous Ca2+ buffer capacity than CA1 neurons, limiting the rise in [Ca2+]i achievable by photolysis. This [Ca2+]i rise induced either a potentiation or a depression at mossy fiber synapses in different preparations. Neither the potentiation nor the depression was accompanied by consistent changes in paired-pulse facilitation, suggesting that these forms of plasticity may be distinct from synaptically induced LTP and LTD at this synapse. Our results are consistent with a postsynaptic locus for the induction of at least some forms of synaptic plasticity at mossy fiber synapses.     

Long-term potentiation of guinea pig mossy fiber responses is not blocked by N-methyl D-aspartate antagonists

Receptors preferentially activated by the excitatory amino acid N-methyl-D-aspartate (NMDA) do not mediate synaptic transmission in the hippocampus but are involved in initiating long-term potentiation (LTP) in hippocampal region CA1. We have examined the role of NMDA receptors in LTP of the commissural/associational and mossy fiber pathways to region CA3 pyramidal neurons. In the commissural/associational pathway, NMDA receptor blockers did not reduce synaptic responses but reversibly blocked the induction of LTP. In contrast, NMDA receptor blockers had no effect on mossy fiber LTP. These results suggest that induction of commissural/associational LTP differs from mossy fiber LTP, although the mechanisms underlying expression of LTP along these pathways could be similar. Kynurenate and L-2-amino-4-phosphonobutyrate, which potently reduce mossy fiber responses, also did not block induction of mossy fiber LTP.     

Pertussis toxin suppresses long-term potentiation of hippocampal mossy fiber synapses

The long-term potentiation (LTP) was studied using rat hippocampal slices in vitro. LTP in mossy fiber-CA3 pyramidal cell synapses was markedly suppressed in slices prepared from rats which had previously received intraventricular injection of pertussis toxin (PTX), compared with the bovine serum albumin-injected controls, suggesting the involvement of G-proteins in the mechanism of LTP in mossy fiber synapses. In contrast, LTP in Schaffer/commissural-CA1 pyramidal synapses was not affected by PTX pretreatment.     

Enhancement of postsynaptic responsiveness during long-term potentiation of mossy fiber synapses in guinea pig hippocampus.

The primary site responsible for the long-lasting enhancement of synaptic transmission during long-term potentiation (LTP) was examined by quantal analysis of excitatory postsynaptic potentials in thin sections of the guinea pig hippocampus. With induction of LTP in mossy fiber synapses, estimated values of quantal amplitude (q) and Pascal parameters p and r were increased significantly. No increases in quantal content (m) were detected. The magnitude of increases in q was almost equal to that of LTP. These results indicate that LTP in mossy fiber synapses results from increases in responsiveness of postsynaptic neurons.     

Separate mechanisms of long-term potentiation in two input systems to CA3 pyramidal neurons of rat hippocampal slices as revealed by the whole-cell patch-clamp technique.

Excitatory synaptic transmission from two input systems to hippocampal CA3 pyramidal neurons was investigated by the whole-cell patch-clamp technique for thin slice preparation, with special reference to long-term potentiation (LTP) in these systems. Excitatory postsynaptic currents (EPSCs) evoked by fimbrial stimulation consisted of two components; one was blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the other was persistent at depolarized membrane potentials and blocked by D-2-amino-5-phosphonovalerate (D-AP5). The contribution of the D-AP5-sensitive component to EPSCs evoked by stimulation of mossy fibers was much less than that to fimbrial EPSCs. High-frequency stimulation of afferent fibers, under current-clamp conditions, elicited LTP. Bath application of D-AP5 blocked the induction of LTP in the fimbrial but not in the mossy fiber synapses. Induction of fimbrial LTP was completely blocked by 10 mM BAPTA applied intracellularly. In contrast, mossy fiber LTP was not blocked by 10 mM BAPTA. Furthermore, mossy fiber LTP, but not fimbrial LTP, was elicited by high-frequency stimulation under voltage-clamp (-80 mV) conditions. These results suggest that activation of NMDA receptors, increase in postsynaptic [Ca2+]i, and postsynaptic membrane depolarization are required for the induction of fimbrial but not for mossy fiber LTP.     

Regional differences in GABAergic modulation for TEA-induced synaptic plasticity in rat hippocampal CA1, CA3 and dentate gyrus

Tetraethylammonium (TEA), a K(+)-channel blocker, reportedly induces long-term potentiation (LTP) of hippocampal CA1 synaptic responses, but at CA3 and the dentate gyrus (DG), the characteristics of TEA-induced plasticity and modulation by inhibitory interneurons remain unclear. This study recorded field EPSPs from CA1, CA3 and DG to examine the involvement of GABAergic modulation in TEA-induced synaptic plasticity for each region. In Schaffer collateral-CA1 synapses and associational fiber (AF)-CA3 synapses, bath application of TEA-induced LTP in the presence and absence of picrotoxin (PTX), a GABA(A) receptor blocker, whereas TEA-induced LTP at mossy fiber (MF)-CA3 synapses was detected only in the absence of GABA(A) receptor blockers. MF-CA3 LTP showed sensitivity to Ni(2+), but not to nifedipine. In DG, synaptic plasticity was modulated by GABAergic inputs, but characteristics differed between the afferent lateral perforant path (LPP) and medial perforant path (MPP). LPP-DG synapses showed TEA-induced LTP during PTX application, whereas at MPP-DG synapses, TEA-induced long-term depression (LTD) was seen in the absence of PTX. This series of results demonstrates that TEA-induced DG and CA3 plasticity displays afferent specificity and is exposed to GABAergic modulation in an opposite manner.     

在脑片水平上突触可塑性长时程增强的研究进展

长时程增强(LTP)是突触效能的重要表现形式,是研究学习与记忆突触机制的客观指标.近年来随着脑片技术的发展,很多关于LTP的实验研究都在脑片水平上进行.介绍了海马脑片CA1区LTP的调节表达机制的研究,海马脑片上诱导产生的LTP的特征和脑片条件的关系,多巴胺转运蛋白阻断剂通过活化D3多巴胺受体增强海马脑片CA1区LTP,以及激活大鼠海马脑片CA1区突触β-肾上腺素能受体增强联合LTP的研究,综述了在脑片水平上研究LTP的诱导表达维持及调节等方面的研究动态和进展.     

M2 muscarinic acetylcholine receptors regulate long-term potentiation at hippocampal CA3 pyramidal cell synapses in an input-specific fashion

Muscarinic receptors have long been known as crucial players in hippocampus-dependent learning and memory, but our understanding of the cellular underpinnings and the receptor subtypes involved lags well behind. This holds in particular for the hippocampal CA3 region, where the mechanisms of synaptic plasticity depend on the type of afferent input. Williams and Johnston (Williams S, Johnston D. Science 242: 84-87, 1988; Williams S, Johnston D. J Neurophysiol 64: 1089-1097, 1990) demonstrated muscarinic depression of mossy fiber (MF) long-term potentiation (LTP) through a presynaptic site of action and Maeda et al. (Maeda T, Kaneko S, Satoh M. Brain Res 619: 324-330, 1993) proposed a bidirectional modulation of MF LTP by muscarinic receptor subtypes. Since then, this issue, as well as muscarinic regulation of plasticity at associational/commissural (A/C) fiber-CA3 synapses has remained largely neglected, not least because of the lack of highly selective ligands for the different muscarinic receptor subtypes. In the present study, we performed field potential and whole cell recordings from the hippocampal CA3 region of M(2) receptor knockout mice to determine the role of M(2) receptors in short-term and long-term plasticity at A/C and MF inputs to CA3 pyramidal cells. At the A/C synapse, M(2) receptors promoted short-term facilitation and LTP. Unexpectedly, M(2) receptors mediated the opposite effect on LTP at the MF synapse, which was significantly reduced, most likely involving a depressant effect of M(2) receptors on adenylyl cyclase activity in MF terminals. Our data demonstrate that cholinergic projections recruit M(2) receptors to redistribute the gain of LTP in CA3 pyramidal cells in an input-specific manner.     

Masking of forskolin-induced long-term potentiation by adenosine accumulation in area CA1 of the rat hippocampus

At hippocampal Schaffer collateral-CA1 synapses, activation of beta-adrenergic receptors and adenylyl cyclase increases transmitter release. However, this effect is transient, which is in contrast to that seen at mossy fiber-CA3 synapses, where activation of cyclic-AMP-dependent protein kinase results in long-lasting facilitation of transmitter release, a phenomenon known as a presynaptic form of long-term potentiation. The present study was aimed at investigating whether forskolin, an adenylyl cyclase activator, could produce long-term effects at the Schaffer collateral-CA1 synapses using extracellular recording techniques. As has been reported previously, forskolin persistently increased the amplitude of evoked population spikes without having a long-term effect on the field excitatory postsynaptic potentials. However, under the conditions where adenosine A1 receptors are inhibited, cyclic-AMP metabolism is disrupted or the transport of cyclic-AMP is blocked, forskolin induces long-term potentiation. Forskolin-induced potentiation is associated with a decrease in paired-pulse facilitation and is blocked by the cyclic-AMP-dependent protein kinase inhibitor Rp-adenosine-3',5'-cyclic monophosphorothioate. Activation of N-methyl-D-aspartate receptors is not required for forskolin-induced long-term potentiation, because pretreatment of slices with the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonovalerate did not prevent forskolin-induced potentiation. These results suggest that blockade of adenosine A1 receptors unmasks forskolin-induced long-term potentiation, and activation of cyclic-AMP-dependent protein kinase induces a form of long-term potentiation which is different from that induced by tetanic stimulation.     

Long-term potentiation in the hippocampal CA1 region does not require insertion and activation of GluR2-lacking AMPA receptors

Activity-dependent insertion of AMPA-type glutamate receptors is thought to underlie long-term potentiation (LTP) at Schaffer collateral fiber synapses on pyramidal cells in the hippocampal CA1 region. Although it is widely accepted that the AMPA receptors at these synapses contain glutamate receptor type 2 (GluR2) subunits, recent findings suggest that LTP in hippocampal slices obtained from 2- to 3-wk-old rodents is dependent on the transient postsynaptic insertion and activation of Ca(2+)-permeable, GluR2-lacking AMPA receptors. Here we examined whether LTP in slices prepared from adult animals exhibits similar properties. In contrast to previously reported findings, pausing synaptic stimulation for as long as 30 min post LTP induction had no effect on LTP maintenance in slices from 2- to 3-mo-old mice. LTP was also not disrupted by postinduction application of a selective blocker of GluR2-lacking AMPA receptors or the broad-spectrum glutamate receptor antagonist kynurenate. Although these results suggest that the role of GluR2-lacking AMPA receptors in LTP might be regulated during postnatal development, LTP in slices obtained from 15- to 21-day-old mice also did not require postinduction synaptic stimulation or activation of GluR2-lacking AMPA receptors. Thus the insertion and activation of GluR2-lacking AMPA receptors do not appear to be fundamental processes involved in LTP at excitatory synapses in the hippocampal CA1 region.     

Heterosynaptic correlates of long-term potentiation induction in hippocampal CA3 neurons

Previous studies have demonstrated that tetanization of hippocampal mossy fibers induces a long-term potentiation of non-tetanized (heterosynaptic) non-mossy fiber afferents (Schaffer collateral/commissural and fimbrial fibers). Tetanization of these non-mossy fiber afferents, in contrast, does not induce mossy fiber long-term potentiation, but induces a long-term depression of mossy fiber responses (Bradler and Barrionuevo, Synapse 4, 132-142, 1989). The synaptic activity necessary to evoke these heterosynaptic alterations of efficacy is not known. Specifically, the dependence of heterosynaptic efficacy on the activation of N-methyl-D-aspartate receptors has not been assessed. In addition, the capability of different afferents to CA3 neurons to support alterations in heterosynaptic efficacy remains largely unknown. In the present study, heterosynaptic alterations of efficacy in the rat did not require the activation of N-methyl-D-aspartate receptors. Mossy fibers supported N-methyl-D-aspartate receptor-independent heterosynaptic long-term depression, and N-methyl-D-aspartate receptor-independent long-term potentiation. In contrast, non-mossy fiber afferents expressed N-methyl-D-aspartate receptor-independent heterosynaptic long-term potentiation induced by a mossy fiber tetanus, and an N-methyl-D-aspartate receptor-independent long-term depression, in addition to N-methyl-D-aspartate receptor-dependent homosynaptic long-term potentiation. The possibility that non-N-methyl-D-aspartate receptor activity in non-tetanized afferents is necessary for heterosynaptic long-term potentiation induction is discussed. Heterosynaptic long-term depression was induced in the absence of homosynaptic long-term potentiation, suggesting that these concomitant forms of synaptic plasticity rely on different mechanisms.     

A Juvenile form of Postsynaptic Hippocampal Long-Term Potentiation in Mice Deficient for the AMPA Receptor Subunit GluR-A

In adult mice, long-term potentiation (LTP) of synaptic transmission at CA3-to-CA1 synapses induced by tetanic stimulation requires l -α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors containing GluR-A subunits. Here, we report a GluR-A-independent form of LTP, which is comparable in size to LTP in wild-type mice at postnatal day 14 (P14) but diminishes between P14 and P42 in brain slices of GluR-A-deficient mice. The GluR-A-independent form of LTP is sensitive to d (−)-2-amino-5-phosphonopentanoic acid ( d -AP5), but lacks short-term potentiation (STP) and can also be observed in the pairing induction protocol. As judged by unaltered paired-pulse facilitation, this LTP form is postsynaptically expressed despite depleted extrasynaptic AMPA receptor pools with reduced levels of GluR-B, which accumulates in somata and synapses of CA1 pyramidal neurons in GluR-A-deficient mice. Our results show that in the developing hippocampus synaptic plasticity can be expressed by AMPA receptors lacking the GluR-A subunit.     

Chronic morphine treatment alters endogenous opioid control of hippocampal mossy fiber synaptic transmission

Synaptic adaptations are thought to be an important component of the consequences of drug abuse. One such adaptation is an up-regulation of adenylyl cyclase that has been shown to increase transmitter release at several inhibitory synapses. In this study the effects of chronic morphine treatment were studied on mossy fiber synapses in the guinea pig hippocampus using extracellular field potential recordings. This opioid-sensitive synapse was chosen because of the known role of the adenylyl cyclase cascade in the regulation of glutamate release. Long-term potentiation (LTP) at the mossy fiber synapse was enhanced after chronic morphine treatment. In control animals, opioid antagonists increased LTP but had no effect in morphine-treated guinea pigs. In contrast, the long-lasting depression of transmission induced by a mGluR agonist and CA1 LTP were not altered. Chronic morphine treatment neither caused tolerance to mu- and kappa-receptor-mediated inhibition at the mossy fiber synapse nor modified total hippocampal dynorphin levels. The results suggest that the phasic inhibition of glutamate transmission mediated by endogenous opioids is reduced after chronic exposure to morphine.     

Noradrenergic enhancement of long-term potentiation at mossy fiber synapses in the hippocampus

1. We tested several hypotheses related to the modulation of long-term potentiation (LTP) by norepinephrine (NE) at the mossy fiber synapses in the rat hippocampal slice preparation using extracellular and intracellular recording techniques. 2. NE exerted frequency-dependent effects on mossy fiber synaptic transmission. It had little effect on extracellular population excitatory postsynaptic potentials (pEPSPs) sampled during low-frequency stimulation, whereas it had marked effects on the duration, magnitude, and probability of induction of LTP at these synapses. 3. The beta-adrenoceptor agonist isoproterenol mimicked all of the effects of NE, whereas the beta-adrenoceptor antagonists propranolol and timolol reversibly blocked the induction of LTP, suggesting the effects of NE are mediated by a beta-adrenoceptor and that beta-adrenoceptor activation may be an important constituent for the expression of LTP at these synapses. 4. Frequency-dependent effects of NE and isoproterenol on mossy fiber pEPSPs were also observed in the presence of the gamma-aminobutyric acid (GABA) antagonist, picrotoxin, suggesting that NE can enhance LTP by a mechanism that does not depend on intact inhibition. However, propranolol did not block LTP in these disinhibited slices and did not affect LTP magnitude. 5. The adenylate cyclase activator forskolin augmented pEPSPs sampled during low-frequency stimulation in disinhibited slices and significantly enhanced LTP. Forskolin, however, did not produce LTP in the absence of tetanic stimulation. This supports the hypothesis that NE and isoproterenol augment features of LTP by stimulating adenosine 3',5'-cyclic monophosphate (cAMP) production and that cAMP plays a modulatory role in the induction of LTP. 6. The postsynaptic injection of the cAMP analogue 8-bromoadenosine 3',5'-cyclic monophosphate (8-bromo-cAMP) significantly increased the probability of induction of LTP measured intracellularly under voltage-clamp conditions with intact inhibition. An analysis of the inhibitory synaptic slope conductance during these experiments indicated that changes in this measure could neither account for the increase in mossy fiber synaptic slope conductance in those cells that displayed it nor account for the group differences in this variable. 7. The amplitude and duration of the postsynaptic depolarization during tetanic stimulation in the cells that displayed LTP in the 8-bromo-cAMP-injected group were significantly greater than in the cells that did not display LTP in the adenosine 5'-monophosphate-injected group.(ABSTRACT TRUNCATED AT 400 WORDS)     

Local protein synthesis and GABAB receptors regulate the reversibility of long-term potentiation at murine hippocampal mossy fibre–CA3 synapses

Reversal of long-term potentiation (LTP) by long trains of low-frequency stimulation is generally referred to as depotentiation. One of the intriguing aspects of depotentiation is that the magnitude of depotentiation is inversely proportional to the time lag of depotentiation stimulation following LTP induction. Although the mechanisms underlying depotentiation have been widely explored, the factors that regulate the susceptibility of LTP to depotentiation stimulation remain largely unclear. We now report that multiple trains of high-frequency stimulation provide immediate synaptic resistance to depotentiation stimulation at the mossy fibre–CA3 synapses. The synaptic resistance to depotentiation stimulation depends on the amount of synaptic stimulation used to induce LTP; it is prevented by protein synthesis inhibitors and is input specific. In contrast, neither the transection of mossy fibre axons near granule cell somata nor the application of RNA synthesis inhibitors influences synaptic resistance to depotentiation stimulation. We also provide evidence that the induction of depotentiation is regulated by GABA_B receptors. Application of a GABA_B receptor antagonist significantly promoted the synaptic resistance to depotentiation stimulation, whereas inhibition of GABA transport delayed the onset of this synaptic resistance. These results suggest that local protein synthesis is required for the development of synaptic resistance to depotentiation stimulation, whereas the activation of GABA_B receptors promotes the susceptibility to depotentiation stimulation. These two factors may crucially regulate the reversal and stability of long-term information storage.     

A proportional but slower NMDA potentiation follows AMPA potentiation in LTP

Most excitatory glutamatergic synapses contain both AMPA and NMDA receptors, but whether these receptors are regulated together or independently during synaptic plasticity has been controversial. Although long-term potentiation (LTP) is thought to selectively enhance AMPA currents and alter the NMDA-to-AMPA ratio, this ratio is well conserved across synapses onto the same neuron. This suggests that the NMDA-to-AMPA ratio is only transiently perturbed by LTP. To test this, we induced LTP at rat neocortical synapses and recorded mixed AMPA-NMDA currents. We observed rapid LTP of AMPA currents, as well as delayed potentiation of NMDA currents that required previous AMPA potentiation. The delayed potentiation of NMDA currents restored the original NMDA-to-AMPA ratio within 2 h of LTP induction. These data suggest that recruitment of AMPA receptors to synapses eventually induces a proportional increase in NMDA current. This may ensure that LTP does not alter the relative contributions of these two receptors to synaptic transmission and information processing.     

Metabotropic glutamate receptor antagonist AIDA blocks induction of mossy fiber-CA3 LTP in vivo

Metabotropic glutamate receptors (mGluR) are implicated in long-term memory storage. mGluR-I and mGluR-II antagonists impede various forms of learning and long-term potentiation (LTP) in animals. Despite the evidence linking mGluR to learning mechanisms, their role in mossy fiber-CA3 long-term potentiation (LTP) is not yet clear. To explain the involvement of mGluR-I in memory mechanisms, we examined the function of the mGluR-I antagonist 1-aminoindan-1, 5-dicarboxylic acid (AIDA) on the induction of mossy fiber-CA3 LTP in vivo in male Sprague Dawley and Fischer 344 (F344) rats. Acute extracellular mossy fiber (MF) responses were evoked by stimulation of the MF bundle and recorded in the stratum lucidum of CA3. The excitatory postsynaptic potential (EPSP) magnitude was measured by using the initial slope of the field EPSP slope measured 2-3 ms after response onset. After collection of baseline MF-CA3 responses at 0.05 Hz, animals received either ((+/-))-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (N-methyl-D-aspartate-R antagonist, 10 mg/kg ip), naloxone (opioid-R antagonist, 10 mg/kg ip), or AIDA (mGluR antagonist, 1 mg/kg ip or 37.5 nmol ic). LTP was induced by two 100-Hz trains at the intensity sufficient to evoke 50% of the maximal response. Responses were collected for an additional 1 h. AIDA blocked induction of LTP in the mossy fiber pathway (P < 0.05) in both strains of rats after systemic and in Sprague Dawley rats after intrahippocampal injection.