8-Cyclopentyltheophylline, an adenosine A1 receptor antagonist, inhibits the reversal of long-term potentiation in hippocampal CA1 neurons
Introduction
Long-term potentiation is a state of persistent synaptic enhancement induced by a brief period of a high-frequency electrical stimulation (tetanus) of afferents (Bliss and Lømo, 1973; Bliss and Gardner-Medwin, 1973). In addition to long-term potentiation, another type of synaptic plasticity, `depotentiation', has been reported, in which low-frequent afferent stimulation (low-frequency stimulation) effectively reverses a pre-established long-term potentiation, both in vivo (Barrioneuvo et al., 1980; Stäubli and Lynch, 1990) and in vitro (Fujii et al., 1991; Bashir and Collingridge, 1994; Stäubli and Lynch, 1996). These activity-dependent synaptic plasticities have been suggested to be responsible for important processes involved in the cellular basis of memory and learning (Collingridge, 1987; Collingridge and Bliss, 1987; Bliss and Collingridge, 1993).
During delivery of input stimulation to hippocampal CA1 neurons, a significant amount of ATP and adenosine derivatives is released from presynaptic terminals into the synaptic cleft in a frequency-dependent manner (White, 1978; Schubert et al., 1979; Wieraszko et al., 1989). In central nervous tissue, adenosine, acting via at least two major classes of adenosine receptors, A1 and A2 (Van Calker et al., 1975; Londos et al., 1980), modulates many physiological functions (Phillis et al., 1975; Snyder, 1985; Durcan and Morgan, 1989; Phillis, 1990). Activation of adenosine A1 receptors inhibits adenylyl cyclase and thereby reduces cyclic AMP formation, while activation of adenosine A2 receptors has the opposite effect (Fredholm et al., 1982; Dunwiddie and Fredholm, 1989; Lupica et al., 1990). In hippocampal neurons, endogenous adenosine and its derivatives, acting via adenosine A1 and/or A2 receptors, are therefore considered to be involved in the mechanism of the frequency-dependent synaptic plasticity, such as long-term potentiation and depotentiation of long-term potentiation.
Arai et al. (1990)have reported that adenosine, acting via adenosine A1 receptors, interrupts long-term potentiation development in hippocampal CA1 neurons. Sekino et al. (1991)have shown that CP-66713, a potent adenosine A2 receptor antagonist (Sarges et al., 1990), prevents long-term potentiation induction in terms of the evoked postsynaptic potential (EPSP), but has no effect on the amplitude of the population spike in CA1 neurons; they therefore suggested that endogenous adenosine, released by tetanic stimulation and acting via adenosine A2 receptors, facilitates long-term potentiation induction in the EPSP but not in the population spike, leading to attenuation of the EPSP-PS dissociation (Taube and Schwartzkroin, 1986). In hippocampal CA1 neurons, CP-66713 is reported to facilitate depotentiation of long-term potentiation in the EPSP but inhibits it in the population spike, indicating that the action of endogenous adenosine in these mechanisms is via activation of adenosine A2 receptors, leading to the attenuation of the EPSP-PS dissociation (Fujii et al., 1992). However, the role of the adenosine A1 receptors in depotentiation of long-term potentiation has not been studied in detail.
In this report, we therefore perfused hippocampal slices with 8-cyclopentyltheophylline (8-CPT), a potent adenosine A1 receptor antagonist (Bruns et al., 1980, Bruns et al., 1987), during the low-frequency stimulation and evaluated the effects on depotentiation of long-term potentiation.
Section snippets
Materials and methods
The techniques used in animal preparation, recording, stimulation, and data analysis were almost identical to those described previously (Fujii et al., 1991). In short, hippocampal slices (500 μm), prepared from adult male guinea pigs (300–400 g), were preincubated in a standard medium, consisting of (in mM): NaCl, 124; KCl, 5.0; NaH2PO4, 1.25; MgSO4, 2.0; CaCl2, 2.5; NaHCO3, 22.0 and glucose, 10.0. in a 95% O2 and 5% CO2 atmosphere at 30–32°C for at least 1 h. A bipolar stimulating electrode
Results
Adenosine A1 receptor antagonists are known to enhance the excitability of CA1 hippocampal neurons (Dunwiddie et al., 1981). In the present study, transiently increased responses were seen when 1 μM 8-CPT was applied for 10 min; these started to increase almost 5 min after beginning of 8-CPT perfusion and declined to the control level within 50–60 min. A typical example is shown in Fig. 1C. 15 to 20 min after wash-out of 8-CPT, the slope of EPSP and amplitude of population spike were 145.6±6.1%
Discussion
In the presence of 1 μM 8-CPT, depotentiation of long-term potentiation both as regards the slope of EPSP and in the amplitude of population spike was blocked in terms of both the percentage reduction of long-term potentiation and the percentage change in long-term potentiation (P<0.01, Fig. 3, DP and 8-CPT+DP). However, to draw this conclusion, the increased response in amplitude induced by 8-CPT by itself must be taken into consideration.
As is shown in Fig. 1C and D, following the perfusion
Acknowledgements
This study was supported by Grants-in Aid from Naito Foundation Natural Science Scholarship to S.F. (No. 96-145).
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