SUMMARY1. Intracellular recording techniques were used to characterize monosynaptic inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) in rat hippocampal slices and to study the mechanism of paired-pulse depression of these synaptic responses. This was achieved by stimulation in stratum radiatum close (< 0 5 mm) to an intracellularly recorded CAI neurone after pharmacological blockade of all excitatory synaptic transmission.2. Under these conditions, low-frequency stimulation (0 033 Hz) evoked a pure biphasic IPSP, which had a short and constant latency to onset. This IPSP was blocked by tetrodotoxin (1 tM) suggesting that it resulted from the electrical stimulation of the axons and/or cell bodies of a monosynaptic inhibitory pathway.3. Picrotoxin (100 /tM) abolished the early component of the biphasic IPSP/C. It left an intact, pure late IPSP/C (IPSP/CB) which had a latency to onset of 29 + 2 ms, latency to peak of 139 +4 ms, a duration of 723+ 135 (range 390-1730) ms and a reversal potential of -93 + 2 mV. The duration was highly dependent on the stimulus intensity whereas the latency to onset was largely independent of the stimulus intensity. The IPSP/CB was reduced or abolished by 1 mM-phaclofen.4. Phaclofen (1 mM) and 2-hydroxy-saclofen (0-1-1-0 mm) reversibly depressed (60-100%) the late component of the biphasic IPSP/C and, where maximally effective, left a pure, early IPSP/C (IPSP/CA). The IPSP/CA had a latency to onset of 3 ms or less, a latency to peak of 17 + 1 ms, a duration of 225 + 3 ms and a reversal potential of -75 + 2 mV.5. Two shocks of identical strength were applied in close succession to characterize, and to study the mechanisms underlying, frequency-dependent depression of inhibitory synaptic responses. Paired-pulse depression was seen for both phases of the biphasic IPSP/C and of the pure IPSP/CB, recorded in the presence of picrotoxin. Paired-pulse depression was not accompanied by changes in the reversal potential of either component, indicating that it was caused by a reduction in the two synaptic conductances. Paired-pulse depression was greater when high stimulus intensities were employed.6. Paired stimuli were applied at separation intervals of between 5 ms and 10 s to determine the temporal profile of frequency-dependent depression. Paired-pulse depression of both IPSCA and IPSCB was most pronounced at an interstimulus MS 7998PHY 424 17 C. H. DAVIES AND OTHERS interval of 100-125 ms and ceased to occur at intervals greater than 5-10 s. Linear summation of IPSCs was seen with intervals of 10 ms or less.7. At rest, (-)-baclofen (5 #M) produced a small hyperpolarization (or outward current) associated with a slight increase in membrane conductance and abolished both components of the inhibitory synaptic response. Effects were stereoselective and reversible. A tenfold lower concentration of (-)-baclofen selectively depressed the synaptic response, causing depressions of 41 + 3 and 54 + 4% for the early and late components, respectively. This effect was reversed by 1 mM-p...

Metabotropic glutamate receptor 1 (mGluR1) is a member of a large family of G-protein-coupled glutamate receptors, the physiological functions of which are largely unknown. Mice deficient in mGluR1 have severe motor coordination and spatial learning deficits. They have no gross anatomical or basic electrophysiological abnormalities in either the cerebellum or hippocampus, but they show impaired cerebellar long-term depression and hippocampal mossy fibre long-term potentiation. mGluR1-deficient mice should therefore be valuable models for studying synaptic plasticity.

Understanding the mechanisms involved in long-term potentiation (LTP) should provide insights into the cellular and molecular basis of learning and memory in vertebrates. It has been established that in the CA1 region of the hippocampus the induction of LTP requires the transient activation of the N-methyl-D-aspartate (NMDA) receptor system. During low-frequency transmission, significant activation of this system is prevented by gamma-aminobutyric acid (GABA) mediated synaptic inhibition which hyperpolarizes neurons into a region where NMDA receptor-operated channels are substantially blocked by Mg2+ (refs. 5, 6). But during high-frequency transmission, mechanisms are evoked that provide sufficient depolarization of the postsynaptic membrane to reduce this block and thereby permit the induction of LTP. We now report that this critical depolarization is enabled because during high-frequency transmission GABA depresses its own release by an action on GABAB autoreceptors, which permits sufficient NMDA receptor activation for the induction of LTP. These findings demonstrate a role for GABAB receptors in synaptic plasticity.