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Metaplasticity of Mossy Fiber Synaptic Transmission Involves Altered Release Probability

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Metaplasticity of Mossy Fiber Synaptic Transmission Involves Altered Release Probability The Journal of Neuroscience, May 1, 2000, 20(9):3434–3441 Metaplasticity of Mossy Fiber Synaptic Transmission Involves Altered Release Probability Ivan V. Goussakov,1 Klaus Fink,2 Christian E. Elger,1 and Heinz Beck1 1Department of Epileptology, University of Bonn, 53105 Bonn, Germany, and 2Department of Pharmacology, University of Bonn, 53113 Bonn, Germany Activity-dependent synaptic plasticity is a fundamental feature but not in kainate-treated animals, indicating that status- of CNS synapses. Intriguingly, the capacity of synapses to induced changes occur downstream of protein kinase A. To test express plastic changes is itself subject to considerable whether altered neurotransmitter release might account for activity-dependent variation, or metaplasticity. These forms of these changes, we measured the size of the releasable pool of higher order plasticity are important because they may be glutamate in mossy fiber terminals. We find that the size of the crucial to maintain synapses within a dynamic functional range. releasable pool of glutamate was significantly increased in In this study, we asked whether neuronal activity induced in vivo kainate-treated rats, indicating an increased release probability by application of kainate can induce lasting changes in mossy at the mossy fiber-CA3 synapse. fiber short- and long-term plasticity. Therefore, we suggest that lasting changes in neurotransmit- Several weeks after kainate-induced status epilepticus, the ter release probability caused by neuronal activity may be a mossy fiber, but not the associational-commissural pathway, powerful mechanism for metaplasticity that modulates both exhibits a marked loss of paired-pulse facilitation, augmenta- short- and long-term plasticity in the mossy fiber-CA3 synapse tion, and long-term potentiation (LTP). Because the adenylyl after status epilepticus. cyclase–protein kinase A cascade is involved in mossy fiber LTP induction, we have tested the integrity of this key pathway Key words: synaptic plasticity; paired-pulse facilitation; by pharmacological activation of either adenylyl cyclase or mossy fiber pathway; long-term potentiation; status epilepticus; protein kinase A. These treatments resulted in LTP in control, release probability The ability to modify synaptic strength in an activity-dependent tion has been described (Bortolotto et al., 1994; Cohen et al., manner, either as long-term depression (LTD) or long-term po- 1998). These phenomena have been described at synapses in tentiation (LTP) is a fundamental feature of most CNS synapses. which LTP is dependent on the activation of NMDA receptors in The properties of different forms of LTP in the rodent hippocam- the postsynaptic neuron, such as at the Schaffer collateral/ pus have been exceedingly well studied. A less well studied but commissural-CA1 synapse. particularly intriguing finding is that the capacity of many syn- A form of LTP distinct from that observed in the CA1 region apses for plastic changes itself is subject to considerable activity- can be observed at the mossy fiber–CA3 synapse. At this synapse, dependent variation, or plasticity. This higher-order plasticity, or LTP induction seems to be independent of postsynaptic depolar- ϩ metaplasticity, may be important in normal function to keep ization or Ca 2 influx through NMDA receptors (Zalutsky and synapses within a dynamic functional range, thus preventing them Nicoll, 1990), but does seem to require an initial rise in postsyn- ϩ from entering states of saturated LTP or LTD (Abraham and aptic Ca 2 , engaging multiple mechanism other than NMDA ϩ Tate, 1997). In addition, such mechanisms may be invoked in receptors, i.e., via voltage-gated Ca 2 channels or intracellular ϩ diseases in which high-frequency discharges of hippocampal neu- Ca2 release (Yeckel et al., 1999). In contrast to LTP induction, rons occur, such as epilepsy. Metaplasticity has been observed the expression or maintenance of fiber LTP seems to involve experimentally as an inhibition of LTP or change in the frequency presynaptic changes in neurotransmitter release (Zalutsky and threshold between LTP and LTD by previous activation of Nicoll, 1990; Nicoll et al., 1994; Xiang et al., 1994; Nicoll and NMDA receptors (Wang and Wagner, 1999). Conversely, a fa- Malenka, 1995). Genetic and pharmacological experiments have cilitation of LTP after metabotropic glutamate receptor activa- successfully uncovered some of the signal transduction pathways important in LTP expression, showing that both production of 2ϩ Received Jan. 3, 2000; revised Feb. 14, 2000; accepted Feb. 17, 2000. cAMP by the Ca -dependent type 1 adenylyl cyclase (Huang et This work was supported by a grant from the Ministry of Science and Education, al., 1994; Villacres et al., 1998) and activation of protein kinase A Nordrhein-Westfalen, a University of Bonn Medical Center grant “BONFOR”, the (Huang et al., 1995; Abel et al., 1997; Castillo et al., 1997) are Sonderforschungsbereich 400 of the Deutsche Forschungsgemeinschaft, the Ger- man–Israel collaborative research program of the Ministry of Science and the necessary in the expression of mossy fiber LTP. In addition to Bundesministerium fur Bildung, Wissenschaft, Forschung und Technologie, and the unique features of LTP, the mossy fiber synapse characteristically graduate program of the Deutsche Forschungsgemeinschaft “Pathogenese von Krankheiten des Nervensystems”. We thank D. Langendo¨rfer, H. Burisch, and M. exhibits paired-pulse facilitation to the second of two closely Reitze for expert technical assistance. spaced stimuli. Paired-pulse facilitation or augmentation are most ϩ Correspondence should be addressed to Dr. Heinz Beck, Department of Epilep- probably caused by a presynaptic accumulation of Ca 2 that tology, University of Bonn Medical Center, Sigmund Freud Strasse 25, D-53105 Bonn, Germany. E-mail: [email protected]. leads to increased transmitter release (Regehr and Tank, 1991; Copyright © 2000 Society for Neuroscience 0270-6474/00/203434-08$15.00/0 Regehr et al., 1994; Salin et al., 1996). Thus, both short- and the Goussakov et al. • Metaplasticity of the Mossy Fiber Synapse J. Neurosci., May 1, 2000, 20(9):3434–3441 3435 expression of long-term plasticity at this synapse involve a change recorded with borosilicate glass microelectrodes (ϳ 2M⍀) filled with in neurotransmitter release. artificial CSF. Signals were amplified with a field potential amplifier (Charite´, Berlin, Germany), filtered at 3 kHz and digitized with a In contrast to NMDA receptor-dependent LTP, it is not known sampling frequency of 10 kHz (ITC-16; Instrutech, Minneola, FL). Data whether mossy fiber LTP shows metaplasticity. We have therefore were then transferred to hard disk for off-line analysis with the TIDA for investigated short- and long-term plasticity at the mossy fiber Windows 3.01 acquisition and analysis package (HEKA Elektronik, synapse several weeks after status epilepticus induced by kainate Lambrecht-Pfalz, Germany). Data were monitored on-line with an oscil- application in vivo. Our data indicate that neuronal activity can loscope (Hameg, Frankfurt, Germany) and a chart recorder (Astro-Med, West Warwick, RI). Data are given as mean Ϯ SEM. cause a lasting change in short- and long-term plasticity via an Preparation of synaptosomes. CA3 regions were dissected from the upregulation of neurotransmitter release probability. hippocampus of male Sprague Dawley rats (220–350 gm; Charles River, Sulzfeld, Germany) according to Hortnagl et al. (1991). Large mossy MATERIALS AND METHODS fiber synaptosomes were prepared as described before (Lonart and Su¨dhof, 1998; Lonart et al., 1998). Isolated CA3 regions were manually Kainate treatment of rats. Adult male Sprague Dawley rats (30–31 d; homogenized in 1 mM MgSO4, 0.3 M sucrose, and 15 mM HEPES at pH 80–140 gm) were injected twice with kainic acid (13.0 mg/kg, i.p.) on 2 7.4 on ice and centrifuged for 10 min at 900 ϫ g. The pellet containing consecutive days. All animals were observed for a time period of 4–6 hr large synaptosomes and nuclei was resuspended in 18% ficoll and 0.3 M after injection. Kainate-treated rats showed an onset of seizure activity sucrose and centrifuged 20 min at 16,000 ϫ g. The supernatant contain- 15–20 min after kainic acid administration. Seizures were rated accord- ing the large synaptosomes was diluted 10 times with 0.3 M sucrose and ing to the scale of Racine (1972). Status epilepticus was defined as centrifuged 20 min at 15,000 ϫ g. The resulting pellet was resuspended continuous limbic motor seizures of stage 2 or higher. Eighty percent of in modified Krebs’ buffer composed of (in mM): NaCl 118, KCl 4.8, the animals showed status epilepticus with bouts of generalized tonic– NaHCO3 25, KH2PO4 1.2, CaCl2 1.3, MgSO4 1.2, D-glucose 11.1, ascor- clonic seizures after the second injection lasting for 1–2 hr. Only these bic acid 0.06, and disodium EDTA 0.03 (equilibrated with 95% O and animals were used for further electrophysiological experiments. After a 2 5% CO2, pH 7.4, 4°C) and kept on ice for 90 min. latent period ranging from 2–3 weeks, spontaneous seizures appeared in Measurement of 3H-glutamate release. To label the readily releasable 3 these animals. To exclude contamination by short-term seizure- glutamate pool, synaptosomes were incubated with 200 nML-[3,4- H]- associated effects, rats were killed only after an 8 hr seizure-free period. glutamic acid (specific activity 44 Ci/mmol; NEN, Dreieich, Germany) Both rats injected with saline vehicle or age-matched control rats were for 5 min at 35°C. Superfusion was performed as described before (Fink used as a control group. and Go¨thert, 1992) with modifications. Aliquots of the labeled synapto- Preparation and recording configuration. Kainate-treated and control somal suspension (final protein content, 363 Ϯ 49 ␮g/ml) were layered on rats were decapitated under chloroform anesthesia. The brain was rapidly Whatman (Maidstone, UK) GF/B filters in chambers and superfused removed and transferred to ice-cold saline (in mM: NaCl 125.0, KCl 3.0, with Krebs’ buffer at 33°C with a flow rate of 0.8 ml/min continuously CaCl2 2.5, MgCl2 1.3, Na2HPO4 1.25, NaHCO3 26.0, and D-glucose 13.0, equilibrated with 95% O2 and 5% CO2.
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