Mossy fibre synaptic NMDA receptors trigger non-Hebbian long-term potentiation at entorhino-CA3 synapses in the rat - PubMed (original) (raw)

Mossy fibre synaptic NMDA receptors trigger non-Hebbian long-term potentiation at entorhino-CA3 synapses in the rat

Masako Tsukamoto et al. J Physiol. 2003.

Abstract

Hippocampal CA3 pyramidal cells receive two independent afferents from the enthorinal cortex, i.e. a direct input via the temporoammonic pathway (TA, perforant path) and an indirect input via the mossy fibres (MF) of dentate granule cells. In spite of past suggestions that the TA is assigned an important role in exciting the pyramidal cells, little is known about their physiological properties. By surgically making an incision through the sulcus hippocampi and a small part of the dentate molecular layer, we succeeded in isolating TA-mediated monosynaptic responses in CA3 stratum lacunosum-moleculare. The TA-CA3 synaptic transmission was completely blocked by a combination of D,L-2-amino-5-phosphonopentanoic acid (AP5) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), NMDA and non-NMDA receptor antagonists, respectively, and displayed paired-pulse facilitation and NMDA receptor-dependent long-term potentiation, which are all typical of glutamatergic synapses. We next addressed the heterosynaptic interaction between TA-CA3 and MF-CA3 synapses. The TA-CA3 transmission was partially attenuated by single-pulse MF pre-stimulation at inter-pulse intervals of up to 70 ms. However, surprisingly, burst stimulation of the MF alone induced long-lasting facilitation of TA-CA3 synaptic efficacy. This non-Hebbian form of synaptic plasticity was efficiently prevented by local application of AP5 into the MF synapse-rich area. Therefore, MF-activated NMDA receptors are responsible for the heterosynaptic modification of TA-CA3 transmission, and thereby, the history of MF activity may be etched into TA-CA3 synaptic strength. Our findings predict a novel form of spatiotemporal information processing in the hippocampus, i.e. a use-dependent intersynaptic memory transfer.

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Figures

Figure 2

Figure 2. Pharmacological characterization of TA–CA3 fEPSPs

A, time courses of TA–CA3 responses following bath application of 50 µ

m

AP5 alone and then both 50 µ

m

AP5 and 20 µ

m

CNQX. Application of AP5 decreased TA–CA3 fEPSPs by 11.1 ± 5.5 %, and the remaining component was completely abolished by additional perfusion with CNQX. These results indicate that basal neurotransmission at TA–CA3 synapses are mediated not only by AMPA receptors but also partly by NMDA receptors. Representative recordings at times −2, 8 and 20 min (marked 1, 2 and 3 in the figure) are shown in the inset. B, Effect of DCG IV on TA–CA3 fEPSPs. Bath perfusion with 1 µ

m

DCG IV attenuated TA responses. Representative recordings at times −2 and 10 min (marked 1 and 2 in the figure) are shown in the inset. The data are summarized in the right panel. The TA was activated at a stimulus intensity that produced either half-maximal or maximal fEPSPs. The suppressive effect of DCG IV did not depend on stimulus intensity. Data represent means ±

s.e.m

. of 5 slices.

Figure 3

Figure 3. Homosynaptic plasticity of TA–CA3 transmission

A, paired-pulse facilitation of TA–CA3 fEPSPs. The ordinate indicates the ratio of the second fEPSP amplitude to the first one at each inter-pulse interval (n = 3–7). A typical field response evoked by paired-pulse stimuli with a 50 ms interval is shown in the inset. B, time course of changes in fEPSP slopes following TA tetanic stimulation (100 Hz for 1 s). The tetanus was delivered to TA in the absence (open circles, n = 7) or presence (closed circles, n = 5) of 50 µ

m

AP5. AP5 was continuously perfused from −10 min to 5 min (open bar). Representative recordings at times 0 and 40 min are shown in the inset. Data represent means ±

s.e.m

. of n cases.

Figure 4

Figure 4. Heterosynaptic modulation of TA–CA3 synaptic transmission by MF inputs

MF (open circles, n = 8) or AC (closed circles, n = 5) was stimulated (each 1 pulse at 300 µA) prior to TA stimulation. The ordinate indicates the ratio of TA-evoked fEPSPs following MF/AC stimulation to control fEPSPs without the prior conditioned stimulus. When the MF stimulus was immediately preceded by TA activation, TA–CA3 transmission was significantly depressed. The depression occurred as a function of the time by which the MF stimulus precedes the TA stimulus. The AC stimulus was virtually ineffective. Representative field potentials with (each lower trace) or without (each upper trace) the conditioned stimulus at an inter-pulse interval of 40 ms are shown in the inset. **P < 0.01_vs._ no conditioned stimulus. Data represent means ±

s.e.m

. of n cases.

Figure 6

Figure 6. No heterosynaptic interaction between other combinations of three CA3 afferents

Two different afferents were alternatively stimulated at 15 s intervals, and tetanic stimulation (100 Hz for 1 s) was delivered to one pathway (open circles) at time 0. A, field responses were recorded from the stratum lacunosum-moleculare. Thus, stimulation of the TA and AC results in a negative-going (sink) field potential and a positive-going (source) field potential, respectively. The afferents to produce sink potentials were set as a tetanized pathway, that is, the tetanized pathway (open circles) was TA, and the control pathway (closed circles) was AC. B, field responses were recorded from the stratum radiatum. The tetanized pathway was AC, and the test pathway was TA. C, field responses were recorded from the stratum radiatum. The tetanized pathway was AC, and the test pathway was MF. D, field responses were recorded from the stratum lucidum. The tetanized pathway was MF, and the test pathway was AC. Although MF-evoked responses did not display marked post-tetanic potentiation, we confirmed that 2 µ

m

DCG IV inhibited these responses. Experiments were repeated with 3–5 slices, producing similar results. Data show one representative case. We did not conduct normalization or averaging because the baseline values, particularly of the test pathway, varied considerably among experiments.

Figure 7

Figure 7. MF activation induces heterosynaptic LTP of TA–CA3, but not TA-CA1, transmission

A, micrograph of a hippocampal slice placed onto a 8 × 8 electrode-array probe, with interelectrode spacing of 150 µm, centred in the apical dendritic field of CA3 pyramidal cells. The electrodes cover the stratum lacunosum-moleculare of CA1 as well as CA3. B, samples of TA-evoked fEPSPs immediately before (blue) and 60 min after (red) MF tetanization (100 Hz for 1 s). Each trace represents an average waveform of 10 successive responses recorded by the location-matched electrode in A. TA stimulation and MF tetanization were applied through the electrodes indicated by the green squares in A. The acceptable level of a defined LTP is a more than 18.7 % increase in fEPSP slopes (asterisks), which corresponds to 2.58 ×

s.d

. of baseline responses (P < 0.01). MF tetanization induced heterosynaptic TA–CA3 LTP but did not affect TA-CA1 fEPSPs. Experiments were repeated with a different seven slices, producing the same results. The scissors and thick black line indicate the incision made in this slice.

Figure 1

Figure 1. Recording of TA–CA3 fEPSPs

A, recording set up. A recording electrode was positioned in CA3 stratum lacunosum-moleculare of a slice incised along the sulcus hippocampi and across the edge of the dentate molecular layer (scissors). Three stimulating electrodes were placed in the proximate of the hippocampal fissure, the stratum granulosum and CA3 stratum radiatum to stimulate TA, MF and AC, respectively. B, representative traces of fEPSPs evoked by applying gradually increased intensity of the TA stimulus, ranging from 10 to 250 µA. _C_-F, input-output relationships of the slope of fEPSPs (C), the amplitude of fEPSPs (D), the width of fEPSPs at half-height (E) and the latency from TA stimulation to reaching the fEPSP peak (F). Almost no shift in the peak latency (only a 21.9 ± 18.7 % decrease) was detected by increasing stimulus intensity, confirming that the fEPSPs reflect TA–CA3 monosynaptic responses. All data represent means ±

s.e.m

. of 24 slices; where no error bars are apparent they have been obscured by the symbol.

Figure 5

Figure 5. Heterosynaptic induction of TA–CA3 LTP by MF inputs

A, time courses of TA–CA3 responses following MF tetanization (100 Hz for 1 s). The tetanus was applied without TA stimulation. TA-evoked fEPSPs gradually increased up to about 200 % and were maintained for at least 60 min. Representative traces at times 0 and 40 min are shown in the inset. After MF tetanus, a TA stimulus that was previously ineffective to evoke a spike elicited spike-relevant responses (arrowhead) in most cases tested (> 90 %), which suggests that MF activation gates TA inputs. B, the average fEPSP slopes from 40 to 60 min after tetanic stimulation of MF (white column, n = 6) or AC (black column, n = 6). A significant increase in TA-evoked fEPSPs was obtained only for MF tetanization. C, in stratum lucidum-transected slices (as shown in the schematic drawing), MF tetanization (100 Hz for 1 s did not cause the induction of heterosynaptic LTP (n = 4). Data represent means ±

s.e.m

. of n cases.

Figure 8

Figure 8. Requirement of activation of NMDA receptors at MF synapses for non-Hebbian TA–CA3 LTP

A, effect of local application of AP5 on MF-induced TA–CA3 LTP. The half-tone meshing in the schematic drawing indicates the drug-perfused area, which includes the stratum lucidum, a MF-terminal zone. Two tetani (each 100 Hz for 1 s) were delivered to MF and then TA at time 0 and 30 min, respectively, in the absence (open circles) or presence (closed circles) of 50 µ

m

AP5 (n = 6). AP5 was twice applied through a silicon microtube each for 15 min during the time indicated by the open bars. AP5 inhibited the induction of MF-evoked, heterosynaptic LTP but not of TA-evoked, homosynaptic LTP. No changes in basal responses were produced by AP5, confirming that the local application successfully separated the TA- and MF-synaptic zones. B, effect of local application of NMDA on TA-evoked fEPSPs. Mg2+-free solution containing 1 m

m

NMDA and 1 µ

m

tetrodotoxin was locally applied for 15 min, causing no apparent change in TA synaptic efficacy (n = 4). Data represent means ±

s.e.m

. of n cases.

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