Cooperative interactions in the induction of long-term potentiation and depression of synaptic excitation between hippocampal CA 3-CA 1 cell pairs in vitro : ( learning / memory / hippocampus / synaptic plasticity )

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Author	Debanne, Dominique Gahwiler, Beat H. Nt, Scorr M. T. H. O. M. P. S. O.
Copyright Year	2005
Abstract	The requirement for cooperative interactions between multiple synaptic inputs in the induction of long-term potentiation (LTP) and long-term depression (LTD) has been tested at Schaffer collateral synapses with paired recordings from monosynaptically coupled CA3-CA1 cell pairs in rat hippocampal slice cultures. Tetanization of single presynaptic neurons at 50 Hz (repeated 5-7 times for 300-500 ms each) induced only a transient potentiation (<3 min) of excitatory postsynaptic potentials (EPSPs). Persistent potentiation (>15 min) was induced only when single presynaptic action potentials were synchronously paired with directly induced postsynaptic depolarizing pulses (repeated 50-100 times). Tetanusinduced potentiation of extracellularly evoked EPSPs lasting >4 min could only be obtained if the EPSP was >4 mV. Because unitary EPSP amplitudes average -1 mV, we conclude that high-frequency discharge must occur synchronously in 4-5 CA3 cells for LTP to be induced in a common postsynaptic CAl cell. Asynchronous pairing of presynaptic action potentials with postsynaptic depolarizing current pulses (preceding each EPSP by 800 ms) depressed both naive and previously potentiated unitary EPSPs. Likewise, homosynaptic LTD of unitary EPSPs was induced when the presynaptic cell was tetanized at 3 Hz for 3 min, regardless oftheir amplitude (0.3-3.2 mV). Homosynaptic LTD of extracellularly evoked Schaffer collateral EPSPs <4 mV could be induced if no inhibitory postsynaptic potential was apparent, but was prevented by eliciting a large inhibitory postsynaptic potential or by injection of hyperpolarizing current in the postsynaptic cell. We conclude that cooperative interactions among multiple excitatory inputs are not required for induction of homosynaptic LTD of unitary EPSPs. Persistent changes in the strength of the synaptic connections between cells are likely to underlie learning and memory formation. Long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission are two alternative forms of synaptic plasticity, providing the best models of these cellular processes. The experimental protocols typically used to induce LTP and LTD, in particular the stimulation of large numbers of fibers to evoke compound synaptic responses, have proven invaluable for studying the fundamental mechanisms by which these phenomena are generated, but may have little relevance to the patterns of activity occurring in the brain during learning and memory. The induction of LTP at Schaffer collateral synapses between hippocampal CA3 and CAl cells requires N-methyl-Daspartate (NMDA) receptor activation and elevation of the postsynaptic Ca2+ concentration (for review, see ref. 1). Associative and cooperative interactions among multiple synaptic inputs have been demonstrated for LTP induction (2-4), and are believed to reflect the requirement that the depolarization of the postsynaptic cell be sufficient to relieve the block of NMDA receptor-gated channels by Mg2+. The number of presynaptic CA3 cells that must discharge synchronously to induce LTP of their synapses with a common postsynaptic CAl cell is not known. The associative induction of LTP at connections between pairs of hippocampal CA3 and CAl neurons has been observed when low-frequency stimulation of the presynaptic neuron is paired with a maintained postsynaptic depolarization (5), but was not observed with high-frequency presynaptic tetani alone (6). The failure to observe tetanus-induced LTP in the latter study could result either because unitary inputs are simply too weak to engage the biochemical machinery responsible for potentiation or because of something intrinsic to the individual synapses studied, such as an inherent nonplasticity. To distinguish between these possibilities, the relative ability of tetanization and synchronous pairing to induce LTP must be compared on the same synaptic connections. The induction ofLTD in the CAl region of the hippocampus also requires NMDA receptor activation and increases in postsynaptic Ca2+ (7-9). LTD can display associative properties (10), and it has recently been concluded that cooperative interactions are required for its induction (11). This conclusion is, however, difficult to reconcile with the successful induction of homosynaptic LTD when only one or a few synapses are stimulated extracellularly (12). We have used dual intracellular recordings from pairs of monosynaptically connected neurons to address several questions. What patterns of activity in a single presynaptic neuron are able to induce changes in synaptic strength? When are cooperative interactions among afferent fibers required to induce LTP and LTD? How many cells must be conjunctively active to induce cooperative changes in synaptic strength? Organotypic hippocampal slice cultures are a favorable preparation with which to perform these experiments because mnonosynaptically coupled CA3-CA1 pyramidal cell pairs may be recorded with high probability (13) and the requirements for LTP and LTD induction in these cultures are identical to those in ex vivo hippocampal slices (9, 10). Furthermore, the amplitude of such unitary excitatory postsynaptic potentials (EPSPs) is more physiological than unitary EPSPs in dissociated hippocampal cell cultures (e.g., ref. 14). MATERIALS AND METHODS Hippocampal slice cultures were prepared and maintained as described (15). In brief, the hippocampi were dissected from 5to Abbreviations: EPSP, excitatory postsynaptic potential; IPSP, inhibitory postsynaptic potential; LTP, long-term potentiation; LTD, longterm depression; NMDA, N-methyl-D-aspartate. *Present address: Unite de Neurocybernetique Cellulaire, Unite Propre de Recherche 9041, Centre National de la Recherche Scientifique, 280 Boulevard Sainte Marguerite, 13009 Marseille, France. tTo whom reprint requests should be addressed. e-mail: thompson@hifo.unizh.ch. 11225 The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. 11226 Neurobiology: Debanne et al. 7-day-old rat pups that were decapitated. Hippocampi were then cut into 400-,um-thick slices that were then attached to glass coverslips in a chicken plasma clot. These coverslips were then placed in individual sealed test-tubes containing semisynthetic medium and maintained on a roller drum in an incubator for 2-4 weeks. After >14 days in vitro, cultures were transferred to a recording chamber mounted on an inverted microscope and were continuously superfused with a warmed (32°C) saline containing 149 mM Na+, 149 mM Cl-, 2.7 mM K+, 2.8 mM Ca2+, 2.0 mM Mg2+, 11.6 mM HCO-, 0.4mM H2PO_, 5.6 mM glucose, and 10 mg/liter Phenol Red (pH = 7.4). Preand postsynaptic cells were impaled in stratum pyramidale using 1 M potassium methylsulfate-filled sharp microelectrodes. EPSPs were recorded from postsynaptic CAl pyramidal cells in response to single evoked action potentials in a presynaptic CA3 pyramidal cell. The criteria for establishing that EPSPs between cell pairs were monosynaptic included relatively short and invariant onset latencies, as described elsewhere (13). The input resistance of the postsynaptic cell was monitored continually during the experiment with short hyperpolarizing current pulses. Analog signals were digitized at 18 kHz and recorded on videotape. Off-line acquisition of 200-500 ms sequences was performed at a digitization rate of 8-10 kHz (AcQuIs1, DIPSI Industrie, Asnieres, France). EPSP amplitudes were measured at fixed latency from the presynaptic action potential in each experiment. Monopolar stimuli (0.1 ms, -5 to -30 ,uA) were delivered from a patch pipette filled with extracellular saline. Values of potentiation and depression were determined from averages of EPSPs over 2-3 min taken 10 min after the end of the pairing procedure or tetanus. Numerical values are given as mean ± SEM. Statistical comparisons were performed with the Mann-Whitney U test.
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