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Application of N-methyl-d -aspartate induces long-term potentiation in the medial perforant path and long-term depression in the lateral perforant path of the rat dentate gyrus in vitro
Neuroscience Letters 298 (2001) 175±178
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Application of N-methyl-d-aspartate induces long-term potentiation in the medial perforant path and long-term depression in the lateral perforant path of the rat dentate gyrus in vitro Anthony M. Rush a, Michael J. Rowan b, Roger Anwyl a,* a Department of Physiology, Trinity College, Dublin 2, Ireland Department of Pharmacology and Therapeutics; Trinity College; Dublin 2, Ireland
b
Received 22 August 2000; received in revised form 30 November 2000; accepted 30 November 2000
Abstract The effect of application of N-methyl-d-aspartate (NMDA) on synaptic plasticity was studied in the medial and lateral perforant path-granule cell synapse in the outer blade of the dentate gyrus in vitro. Field excitatory post-synaptic potentials were recorded from the middle or outer molecular layer in response to stimulation of the medial or lateral perforant path. Bath perfusion of NMDA (10 mM, 5 min) resulted in induction of long-term potentiation in the medial perforant path, and induction of long-term depression in the lateral perforant path. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Long-term potentiation; Long-term depression; Dentate gyrus; N-Methyl-d-aspartate
It is now well established that long-lasting changes in glutamatergic synaptic transmission can be induced by appropriate stimulation in many areas of the mammalian brain [3]. Two forms of synaptic plasticity have been particularly frequently studied, long-term potentiation (LTP) [4] and long-term depression (LTD) [7,16], which are induced by brief high frequency stimulation (HFS) and prolonged low frequency stimulation (LFS), respectively. Both LTP and LTD have forms that are dependent upon activation of N-methyl-d-aspartate (NMDA) receptors, and accordingly they are inhibited by the NMDA receptor antagonist d-2-amino-5-phosphonopentanoate (d-AP5) [6,7,16]. Brief application of NMDA in control physiological media has been shown in several previous studies in CA1 to induce either a transient depression of the test ®eld excitatory postsynaptic potential (EPSP) followed by a short-lasting potentiation [6,9,14,15], or recently, LTD [10]. However, NMDA has not been shown to induce LTP when applied in control physiological media. In the present studies, the effect of NMDA application has been investigated in the medial and lateral perforant paths of the dentate gyrus in vitro. We show that NMDA perfusion has a differing effect on * Corresponding author. Tel.: 1353-1-6081-624; fax: 1353-1679-3545. E-mail address: [email protected] (R. Anwyl).
plasticity in the medial and lateral perforant paths, inducing LTP in the former and LTD in the latter. All experiments were carried out on transverse slices of the rat hippocampus (age 3±4 weeks, weight 40±80 g). The brains were rapidly removed after decapitation and placed in cold oxygenated (95% O2/5% CO2) media. Slices were cut at a thickness of 350 mm using a Campden vibroslice, and placed in a storage container containing oxygenated media at room temperature (20±228C). The slices were then transferred as required to a recording chamber for submerged slices and continuously superfused at a rate of 5±7 ml/min at 30±328C. The control media contained: (mM) NaCl 120; KCl 2.5; NaH2PO4 1.25; NaHCO3 26; MgSO4 2.0; CaCl2 2.0; d-glucose 10. All solutions contained 50 mM picrotoxin (Sigma) to block g-aminobutyric acidA-mediated activity. EPSPs were recorded in the medial and lateral perforant pathway in the outer blade of the dentate gyrus. Standard electrophysiological techniques were used to record ®eld potentials. Presynaptic stimulation was applied to the medial or lateral perforant pathway of the dentate gyrus, and ®eld EPSPs were recorded at a control test frequency of 0.033 or 0.0166 Hz from the middle or outer one-third of the molecular layer of the dentate gyrus. To check pathway speci®city, paired-pulse stimuli were given (40 ms apart) and paired-pulse depression or facilitation used as criteria to con®rm correct placement in the medial or lateral perforant pathways, respectively. In
0304-3940/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 0) 01 74 2- 0
176
A.M. Rush et al. / Neuroscience Letters 298 (2001) 175±178
Fig. 1. NMDA induces LTP in the medial perforant path of the dentate gyrus in vitro. (A) Bath perfusion of NMDA (10 mM, 5 min) induced an initial small non-signi®cant depression followed, upon washout of the NMDA, a signi®cant LTP measuring 21 ^ 5%, n 6. (B) Repeat applications of NMDA induced additional LTP which reached a maximum of 31 ^ 11%, n 6. Subsequent HFS was still able to induce large additional LTP. (C) HFS-induced LTP following NMDA induced LTP of 58 ^ 7%, n 6 (open circles) has a very similar amplitude to control HFS-induced LTP of 50 ^ 6%, n 7 (®lled circles). (D) Cessation of test stimulation during application of NMDA still resulted in induction of LTP. (E) Paired pulse depression was not signi®cantly altered by induction of NMDA-mediated LTP.
A.M. Rush et al. / Neuroscience Letters 298 (2001) 175±178
each experiment, an input-output curve (afferent stimulus intensity versus EPSP amplitude) was plotted at the test frequency. For all experiments, the amplitude of the test EPSP was adjusted to one-third of maximum, usually about 1±1.2 mV. LTP/LTD was measured at 25±30 min post NMDA application. HFS-induced LTP was induced by eight trains each of eight stimuli at 200 Hz, intertrain interval 0.2 s. NMDA was obtained from Sigma. Recordings were analyzed using p-Clamp. Values are the mean ^ SEM for n slices and two-tailed Student's t-test was used for statistical comparison. In previous experiments in CA1, perfusion of a relatively high concentration (150 mM) of NMDA for a brief time induced a large transient depression followed by a transient potentiation [14,15]. Similar ®ndings were observed in the present study in the dentate gyrus using a high concentration of NMDA for a brief time. More recent work in CA1 showed that longer bath application of NMDA (20 mM for 3 min) induced a STD, followed by a LTD [10]. We therefore investigated the effect of a lower concentration of NMDA (10±20 mM) perfused for a longer period (5 min) in the dentate. In the initial set of experiments, recordings were made from the medial perforant path. Bath perfusion of NMDA (10 mM, 5 min) caused a small (1±5%) but non-signi®cant depression of the EPSP during the actual perfusion, followed, upon washout, by an increasing enhancement of the EPSP over the subsequent 10 min and then induction of a stable LTP measuring 21 ^ 5% (n 6) (Fig. 1A). Repeat applications of NMDA induced additional LTP, with the NMDA-induced LTP reaching a maximum of 31 ^ 11%; n 6 after the third application of NMDA (Fig. 1B). Such NMDA-induced LTP did not occlude HFS induced LTP. Thus control HFSinduced LTP measured 50 ^ 6%; n 7 (Fig. 1C). Following maximal induction of LTP by NMDA application, the magnitude of HFS-induced LTP was not altered, measuring 58 ^ 7%; n 6 (Fig. 1B,C). Stimulation during the application of NMDA was not found to be necessary for the induction of LTP. Thus cessation of test stimulation during and 15 min after the perfusion of NMDA did not inhibit the induction of LTP, which measured 19 ^ 3; n 5 (Fig. 1D). In the medial perforant path, paired stimuli applied at 40 ms interpulse interval results in paired pulse depression of the EPSP of 16 ^ 3%; n 6. The paired pulse depression was reduced in the presence of NMDA, to 5 ^ 4%, but following washout of NMDA, returned to the control level, i.e. no change in paired pulse depression accompanied NMDA induced LTP (Fig. 1E). Recordings from the lateral perforant path showed that application of NMDA had a very different action to that in the medial perforant path. Thus perfusion of NMDA (10 mM, 5 min) induced LTD of the test EPSP. The LTD induced by a single application of NMDA was small and not signi®cant. However, additional applications of NMDA produced a summation of the LTD, and LTD became prominent, measuring 25 ^ 5%; n 4, after the 2nd to 4th application (Fig. 2).
177
The present study demonstrates that the plasticity evoked by NMDA has a regional speci®city. In the medial perforant path of the dentate gyrus, NMDA induces LTP, whereas in the lateral perforant path, NMDA induces LTD. The ®nding that NMDA application can induce LTP in the medial perforant path is the ®rst such observation of NMDA-induced LTP. Previous studies have shown that NMDA application induces either only a short-term potentiation when relatively high concentrations of NMDA were applied for a brief time either [6,9,14,15] or LTD when low concentrations of NMDA were applied for a longer time [10]. The induction of LTP by NMDA in the medial perforant path in the present study, rather than short-term potentiation, is likely to be due to the application of NMDA at a low concentration and for a relatively prolonged period. Interestingly, the LTP induced by exogenous NMDA application did not occlude with HFSinduced LTP. This could be due to different sites of induction of the LTP induced by exogenous NMDA application and by HFS. For example, perhaps exogenous NMDA application results in a presynaptic site for LTP induction via activation of presynaptic NMDAR [5] or NMDA receptors located on astrocytes, as suggested by Araque et al. [1], in contrast to HFS inducing LTP at a post-synaptic site. As no measurable changes in paired-pulse depression accompanied the LTP induced by exogenous NMDA application, such LTP, if presynaptic, would involve a change in the number of sites of release rather than a change in release probability. The detailed mechanisms of induction of the LTP induced by exogenous NMDA are presently under investigation. The induction of LTD by NMDA application in the lateral perforant path is identical to that found in the study [10] in CA1, in which a similar concentration and duration of application of NMDA to the present study was used. It is well established that Ca 21 in¯ux via NMDA receptor
Fig. 2. NMDA induces LTD in the lateral perforant path of the dentate gyrus in vitro. An initial application of NMDA by bath perfusion did not induce LTD, but further applications induced signi®cant LTD measuring 25 ^ 5, n 4, after the 4th application of NMDA.
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A.M. Rush et al. / Neuroscience Letters 298 (2001) 175±178
is required to trigger the induction of NMDA receptor-dependent LTP and LTD [2,12,13]. According to the differential threshold hypothesis, LTP has a high intrinsic Ca 21 threshold and is induced by a large rise in Ca 21, whereas LTD has a low intrinsic Ca 21 threshold and is selectively induced by a lower rise in Ca 21 [2,11]. Measurements of Ca 21 increase induced by stimulation protocols that induce either LTP or LTD have supported this theory [8,17,18]. We postulate that the difference in plasticity induced by NMDA in the two paths, i.e. induction of LTP in the medial perforant path, and LTD in the lateral perforant path is due to a differential increase in intracellular Ca 21 in the two paths produced by NMDA application. Thus NMDA would evoke a large increase in postsynaptic intracellular Ca 21 at the synapses in the medial perforant path which would result in induction of LTP, and evoke a small increase in Ca 21 in the lateral perforant path which would result in the induction of LTD. A mechanism for such a difference in Ca 21 in¯ux could arise as a result of a difference in the properties of the NMDA receptors, and therefore of the time course or voltage-dependence of the NMDA receptor mediated currents, at synapses in the medial and lateral perforant paths. We would like to thank the Wellcome Trust for ®nancial support. [1] Araque, A., Sanzgiri, R.P., Parpura, V. and Haydon, P.G., Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons, J. Neurosci., 18 (1998) 6822±6829. [2] Artola, A. and Singer, W., Long-term depression of excitatory synaptic depression and its relationship to long-term potentiation, Trends Neurosci., 16 (1993) 480±487. [3] Bliss, T.V.P. and Collingridge, G.L., A synaptic model of memory: long-term potentiation in the hippocampus, Nature, 361 (1993) 31±39. [4] Bliss, T.V. and Lomo, T., Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetised rabbit following stimulation of the perforant path, J. Physiol., 232 (1973) 331±356. [5] Casado, M., Dieudonne, S. and Ascher, P., Presynaptic
[6] [7]
[8]
[9] [10]
[11] [12]
[13] [14]
[15] [16] [17]
[18]
N-methyl-d-aspartate receptors at the parallel ®ber-Purkinje cell synapse, Proc. Natl. Acad. Sci., 97 (2000) 11593±11597. Collingridge, G.L., Kehl, S.J. and McLennan, H., The antagonism of amino acid induced excitations of rat hippocampal CA1 neurons in vitro, J. Physiol., 334 (1983) 19±31. Dudek, S.M. and Bear, M.F., Homosynaptic long-term depression in area CA1 of the hippocampus and effects of N-methyl-d-aspartate receptor blockade, Proc. Natl. Acad. Sci. USA, 89 (1992) 4363±4367. Hansel, C., Artola, A. and Singer, W., Relation between dendritic Ca 21 levels and the polarity of synaptic longterm modi®cations in rat visual cortex neurons, Eur. J. Neurosci., 9 (1997) 2309±2322. Kauer, J.A., Malenka, R.C. and Nicoll, R.A., NMDA application potentiates synaptic transmission in the hippocampus, Nature, 334 (1988) 250±252. Lee, H-Y., Kameyama, K., Huganir, R.L. and Bear, M.F., NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus, Neuron, 21 (1998) 1151±1162. Lisman, J., A mechanism for the Hebb and anti-Hebb processes underlying learning and memory, Proc. Natl. Acad. Sci., 86 (1989) 9574±9578. Lynch, G., Larson, J., Kelso, S., Barrionuevo, G. and Schottler, F., Intracellular injections of EGTA block induction of hippocampal long-term potentiation, Nature, 305 (1983) 719±772. Malenka, R.C., Kauer, J.A., Zucker, R.S. and Nicoll, R.A., Post-synaptic calcium is suf®cient for potentiation of hippocampal synaptic transmission, Science, 242 (1988) 81±84. McGuinness, N., Anwyl, R. and Rowan, M., The effects of external calcium on the N-methyl-d-aspartate induced short-term potentiation in the rat hippocampal slice, Neurosci. Lett., 131 (1991) 13±16. McGuinness, N., Anwyl, R. and Rowan, M., Inhibition of an N-methyl-d-aspartate induced short-term potentiation in the rat hippocampal slice, Brain Res., 562 (1991) 335±338. Mulkey, R.M. and Malenka, R.C., Mechanisms underlying induction of homosynaptic long-term depression in area CA1 of the hippocampus, Neuron, 9 (1992) 967±975. Otani, S. and Connor, J.A., Requirement of rapid Ca entry and synaptic activation of metabotropic glutamate receptors for the induction of long-term depression in adult rat hippocampus, J. Physiol., 511 (1998) 761±770. Yang, S-N, Tang, Y-G and Zucker, R.S., Selective induction of LTP and LTD by post-synaptic [Ca 21]i elevation, J. Neurophysiol., 81 (1999) 781±787.
www.elsevier.com/locate/neulet
Application of N-methyl-d-aspartate induces long-term potentiation in the medial perforant path and long-term depression in the lateral perforant path of the rat dentate gyrus in vitro Anthony M. Rush a, Michael J. Rowan b, Roger Anwyl a,* a Department of Physiology, Trinity College, Dublin 2, Ireland Department of Pharmacology and Therapeutics; Trinity College; Dublin 2, Ireland
b
Received 22 August 2000; received in revised form 30 November 2000; accepted 30 November 2000
Abstract The effect of application of N-methyl-d-aspartate (NMDA) on synaptic plasticity was studied in the medial and lateral perforant path-granule cell synapse in the outer blade of the dentate gyrus in vitro. Field excitatory post-synaptic potentials were recorded from the middle or outer molecular layer in response to stimulation of the medial or lateral perforant path. Bath perfusion of NMDA (10 mM, 5 min) resulted in induction of long-term potentiation in the medial perforant path, and induction of long-term depression in the lateral perforant path. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Long-term potentiation; Long-term depression; Dentate gyrus; N-Methyl-d-aspartate
It is now well established that long-lasting changes in glutamatergic synaptic transmission can be induced by appropriate stimulation in many areas of the mammalian brain [3]. Two forms of synaptic plasticity have been particularly frequently studied, long-term potentiation (LTP) [4] and long-term depression (LTD) [7,16], which are induced by brief high frequency stimulation (HFS) and prolonged low frequency stimulation (LFS), respectively. Both LTP and LTD have forms that are dependent upon activation of N-methyl-d-aspartate (NMDA) receptors, and accordingly they are inhibited by the NMDA receptor antagonist d-2-amino-5-phosphonopentanoate (d-AP5) [6,7,16]. Brief application of NMDA in control physiological media has been shown in several previous studies in CA1 to induce either a transient depression of the test ®eld excitatory postsynaptic potential (EPSP) followed by a short-lasting potentiation [6,9,14,15], or recently, LTD [10]. However, NMDA has not been shown to induce LTP when applied in control physiological media. In the present studies, the effect of NMDA application has been investigated in the medial and lateral perforant paths of the dentate gyrus in vitro. We show that NMDA perfusion has a differing effect on * Corresponding author. Tel.: 1353-1-6081-624; fax: 1353-1679-3545. E-mail address: [email protected] (R. Anwyl).
plasticity in the medial and lateral perforant paths, inducing LTP in the former and LTD in the latter. All experiments were carried out on transverse slices of the rat hippocampus (age 3±4 weeks, weight 40±80 g). The brains were rapidly removed after decapitation and placed in cold oxygenated (95% O2/5% CO2) media. Slices were cut at a thickness of 350 mm using a Campden vibroslice, and placed in a storage container containing oxygenated media at room temperature (20±228C). The slices were then transferred as required to a recording chamber for submerged slices and continuously superfused at a rate of 5±7 ml/min at 30±328C. The control media contained: (mM) NaCl 120; KCl 2.5; NaH2PO4 1.25; NaHCO3 26; MgSO4 2.0; CaCl2 2.0; d-glucose 10. All solutions contained 50 mM picrotoxin (Sigma) to block g-aminobutyric acidA-mediated activity. EPSPs were recorded in the medial and lateral perforant pathway in the outer blade of the dentate gyrus. Standard electrophysiological techniques were used to record ®eld potentials. Presynaptic stimulation was applied to the medial or lateral perforant pathway of the dentate gyrus, and ®eld EPSPs were recorded at a control test frequency of 0.033 or 0.0166 Hz from the middle or outer one-third of the molecular layer of the dentate gyrus. To check pathway speci®city, paired-pulse stimuli were given (40 ms apart) and paired-pulse depression or facilitation used as criteria to con®rm correct placement in the medial or lateral perforant pathways, respectively. In
0304-3940/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 0) 01 74 2- 0
176
A.M. Rush et al. / Neuroscience Letters 298 (2001) 175±178
Fig. 1. NMDA induces LTP in the medial perforant path of the dentate gyrus in vitro. (A) Bath perfusion of NMDA (10 mM, 5 min) induced an initial small non-signi®cant depression followed, upon washout of the NMDA, a signi®cant LTP measuring 21 ^ 5%, n 6. (B) Repeat applications of NMDA induced additional LTP which reached a maximum of 31 ^ 11%, n 6. Subsequent HFS was still able to induce large additional LTP. (C) HFS-induced LTP following NMDA induced LTP of 58 ^ 7%, n 6 (open circles) has a very similar amplitude to control HFS-induced LTP of 50 ^ 6%, n 7 (®lled circles). (D) Cessation of test stimulation during application of NMDA still resulted in induction of LTP. (E) Paired pulse depression was not signi®cantly altered by induction of NMDA-mediated LTP.
A.M. Rush et al. / Neuroscience Letters 298 (2001) 175±178
each experiment, an input-output curve (afferent stimulus intensity versus EPSP amplitude) was plotted at the test frequency. For all experiments, the amplitude of the test EPSP was adjusted to one-third of maximum, usually about 1±1.2 mV. LTP/LTD was measured at 25±30 min post NMDA application. HFS-induced LTP was induced by eight trains each of eight stimuli at 200 Hz, intertrain interval 0.2 s. NMDA was obtained from Sigma. Recordings were analyzed using p-Clamp. Values are the mean ^ SEM for n slices and two-tailed Student's t-test was used for statistical comparison. In previous experiments in CA1, perfusion of a relatively high concentration (150 mM) of NMDA for a brief time induced a large transient depression followed by a transient potentiation [14,15]. Similar ®ndings were observed in the present study in the dentate gyrus using a high concentration of NMDA for a brief time. More recent work in CA1 showed that longer bath application of NMDA (20 mM for 3 min) induced a STD, followed by a LTD [10]. We therefore investigated the effect of a lower concentration of NMDA (10±20 mM) perfused for a longer period (5 min) in the dentate. In the initial set of experiments, recordings were made from the medial perforant path. Bath perfusion of NMDA (10 mM, 5 min) caused a small (1±5%) but non-signi®cant depression of the EPSP during the actual perfusion, followed, upon washout, by an increasing enhancement of the EPSP over the subsequent 10 min and then induction of a stable LTP measuring 21 ^ 5% (n 6) (Fig. 1A). Repeat applications of NMDA induced additional LTP, with the NMDA-induced LTP reaching a maximum of 31 ^ 11%; n 6 after the third application of NMDA (Fig. 1B). Such NMDA-induced LTP did not occlude HFS induced LTP. Thus control HFSinduced LTP measured 50 ^ 6%; n 7 (Fig. 1C). Following maximal induction of LTP by NMDA application, the magnitude of HFS-induced LTP was not altered, measuring 58 ^ 7%; n 6 (Fig. 1B,C). Stimulation during the application of NMDA was not found to be necessary for the induction of LTP. Thus cessation of test stimulation during and 15 min after the perfusion of NMDA did not inhibit the induction of LTP, which measured 19 ^ 3; n 5 (Fig. 1D). In the medial perforant path, paired stimuli applied at 40 ms interpulse interval results in paired pulse depression of the EPSP of 16 ^ 3%; n 6. The paired pulse depression was reduced in the presence of NMDA, to 5 ^ 4%, but following washout of NMDA, returned to the control level, i.e. no change in paired pulse depression accompanied NMDA induced LTP (Fig. 1E). Recordings from the lateral perforant path showed that application of NMDA had a very different action to that in the medial perforant path. Thus perfusion of NMDA (10 mM, 5 min) induced LTD of the test EPSP. The LTD induced by a single application of NMDA was small and not signi®cant. However, additional applications of NMDA produced a summation of the LTD, and LTD became prominent, measuring 25 ^ 5%; n 4, after the 2nd to 4th application (Fig. 2).
177
The present study demonstrates that the plasticity evoked by NMDA has a regional speci®city. In the medial perforant path of the dentate gyrus, NMDA induces LTP, whereas in the lateral perforant path, NMDA induces LTD. The ®nding that NMDA application can induce LTP in the medial perforant path is the ®rst such observation of NMDA-induced LTP. Previous studies have shown that NMDA application induces either only a short-term potentiation when relatively high concentrations of NMDA were applied for a brief time either [6,9,14,15] or LTD when low concentrations of NMDA were applied for a longer time [10]. The induction of LTP by NMDA in the medial perforant path in the present study, rather than short-term potentiation, is likely to be due to the application of NMDA at a low concentration and for a relatively prolonged period. Interestingly, the LTP induced by exogenous NMDA application did not occlude with HFSinduced LTP. This could be due to different sites of induction of the LTP induced by exogenous NMDA application and by HFS. For example, perhaps exogenous NMDA application results in a presynaptic site for LTP induction via activation of presynaptic NMDAR [5] or NMDA receptors located on astrocytes, as suggested by Araque et al. [1], in contrast to HFS inducing LTP at a post-synaptic site. As no measurable changes in paired-pulse depression accompanied the LTP induced by exogenous NMDA application, such LTP, if presynaptic, would involve a change in the number of sites of release rather than a change in release probability. The detailed mechanisms of induction of the LTP induced by exogenous NMDA are presently under investigation. The induction of LTD by NMDA application in the lateral perforant path is identical to that found in the study [10] in CA1, in which a similar concentration and duration of application of NMDA to the present study was used. It is well established that Ca 21 in¯ux via NMDA receptor
Fig. 2. NMDA induces LTD in the lateral perforant path of the dentate gyrus in vitro. An initial application of NMDA by bath perfusion did not induce LTD, but further applications induced signi®cant LTD measuring 25 ^ 5, n 4, after the 4th application of NMDA.
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A.M. Rush et al. / Neuroscience Letters 298 (2001) 175±178
is required to trigger the induction of NMDA receptor-dependent LTP and LTD [2,12,13]. According to the differential threshold hypothesis, LTP has a high intrinsic Ca 21 threshold and is induced by a large rise in Ca 21, whereas LTD has a low intrinsic Ca 21 threshold and is selectively induced by a lower rise in Ca 21 [2,11]. Measurements of Ca 21 increase induced by stimulation protocols that induce either LTP or LTD have supported this theory [8,17,18]. We postulate that the difference in plasticity induced by NMDA in the two paths, i.e. induction of LTP in the medial perforant path, and LTD in the lateral perforant path is due to a differential increase in intracellular Ca 21 in the two paths produced by NMDA application. Thus NMDA would evoke a large increase in postsynaptic intracellular Ca 21 at the synapses in the medial perforant path which would result in induction of LTP, and evoke a small increase in Ca 21 in the lateral perforant path which would result in the induction of LTD. A mechanism for such a difference in Ca 21 in¯ux could arise as a result of a difference in the properties of the NMDA receptors, and therefore of the time course or voltage-dependence of the NMDA receptor mediated currents, at synapses in the medial and lateral perforant paths. We would like to thank the Wellcome Trust for ®nancial support. [1] Araque, A., Sanzgiri, R.P., Parpura, V. and Haydon, P.G., Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons, J. Neurosci., 18 (1998) 6822±6829. [2] Artola, A. and Singer, W., Long-term depression of excitatory synaptic depression and its relationship to long-term potentiation, Trends Neurosci., 16 (1993) 480±487. [3] Bliss, T.V.P. and Collingridge, G.L., A synaptic model of memory: long-term potentiation in the hippocampus, Nature, 361 (1993) 31±39. [4] Bliss, T.V. and Lomo, T., Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetised rabbit following stimulation of the perforant path, J. Physiol., 232 (1973) 331±356. [5] Casado, M., Dieudonne, S. and Ascher, P., Presynaptic
[6] [7]
[8]
[9] [10]
[11] [12]
[13] [14]
[15] [16] [17]
[18]
N-methyl-d-aspartate receptors at the parallel ®ber-Purkinje cell synapse, Proc. Natl. Acad. Sci., 97 (2000) 11593±11597. Collingridge, G.L., Kehl, S.J. and McLennan, H., The antagonism of amino acid induced excitations of rat hippocampal CA1 neurons in vitro, J. Physiol., 334 (1983) 19±31. Dudek, S.M. and Bear, M.F., Homosynaptic long-term depression in area CA1 of the hippocampus and effects of N-methyl-d-aspartate receptor blockade, Proc. Natl. Acad. Sci. USA, 89 (1992) 4363±4367. Hansel, C., Artola, A. and Singer, W., Relation between dendritic Ca 21 levels and the polarity of synaptic longterm modi®cations in rat visual cortex neurons, Eur. J. Neurosci., 9 (1997) 2309±2322. Kauer, J.A., Malenka, R.C. and Nicoll, R.A., NMDA application potentiates synaptic transmission in the hippocampus, Nature, 334 (1988) 250±252. Lee, H-Y., Kameyama, K., Huganir, R.L. and Bear, M.F., NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus, Neuron, 21 (1998) 1151±1162. Lisman, J., A mechanism for the Hebb and anti-Hebb processes underlying learning and memory, Proc. Natl. Acad. Sci., 86 (1989) 9574±9578. Lynch, G., Larson, J., Kelso, S., Barrionuevo, G. and Schottler, F., Intracellular injections of EGTA block induction of hippocampal long-term potentiation, Nature, 305 (1983) 719±772. Malenka, R.C., Kauer, J.A., Zucker, R.S. and Nicoll, R.A., Post-synaptic calcium is suf®cient for potentiation of hippocampal synaptic transmission, Science, 242 (1988) 81±84. McGuinness, N., Anwyl, R. and Rowan, M., The effects of external calcium on the N-methyl-d-aspartate induced short-term potentiation in the rat hippocampal slice, Neurosci. Lett., 131 (1991) 13±16. McGuinness, N., Anwyl, R. and Rowan, M., Inhibition of an N-methyl-d-aspartate induced short-term potentiation in the rat hippocampal slice, Brain Res., 562 (1991) 335±338. Mulkey, R.M. and Malenka, R.C., Mechanisms underlying induction of homosynaptic long-term depression in area CA1 of the hippocampus, Neuron, 9 (1992) 967±975. Otani, S. and Connor, J.A., Requirement of rapid Ca entry and synaptic activation of metabotropic glutamate receptors for the induction of long-term depression in adult rat hippocampus, J. Physiol., 511 (1998) 761±770. Yang, S-N, Tang, Y-G and Zucker, R.S., Selective induction of LTP and LTD by post-synaptic [Ca 21]i elevation, J. Neurophysiol., 81 (1999) 781±787.