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The Journal of Neuroscience, June 1, 1999, 19(11):4609-4615

GABA_B Receptor Antagonism: Facilitatory Effects on Memory Parallel Those on LTP Induced by TBS but Not HFS

Ursula Stäubli, Joey Scafidi, and Daniel Chun

Center for Neural Science, New York University, New York, New York 10003

The present experiments used CGP 35348, a selective GABA_B receptor antagonist with a significantly higher affinity for post- versus presynaptic receptors, to dissociate the role of antagonist concentration versus stimulation mode in determining whether GABA_B receptor blockade facilitates or suppresses long-term potentiation (LTP). The antagonist was applied by pressure ejection to one of two recording sites in area CA1 of hippocampal slices before LTP was induced at both sites with either theta burst or high-frequency stimulation (TBS or HFS). TBS produced a dose-dependent facilitation of potentiation that turned into depression at the highest concentration tested, a result reflecting the dose-dependent balance between the drug's postsynaptic disinhibitory effect and its action on presynaptic autoreceptors regulating the release of GABA. In contrast, HFS-induced LTP increased monotonically with drug concentration, suggesting that blockade of postsynaptic GABA_B receptors is the only factor contributing to HFS-induced LTP. To test the relevance of the two sets of LTP results, we performed behavioral studies examining the effect of different dosages of antagonist on spatial retention and found that memory was enhanced at intermediate dosages but not at very low and high concentrations, reminiscent of the bell-shaped dose-response curve obtained for TBS-induced LTP. These findings are consistent with the notion that LTP induced by electrical stimulation modeled after endogenous theta-modulated activity patterns bears more relevance to behavior than does potentiation induced by arbitrary tetanic trains.

Key words: LTP; memory; hippocampus; theta; GABA_B; autoreceptors; postsynaptic; facilitation; impairment; dose-response curve

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19114609-07$05.00/0

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