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The Journal of Neurophysiology Vol. 81 No. 4 April 1999, pp. 1626-1635
Copyright ©1999 by the American Physiological Society
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037
Tallent, Melanie K. and
George R. Siggins.
Somatostatin acts in CA1 and CA3 to reduce hippocampal epileptiform
activity. Although the peptide somatostatin (SST) has been
speculated to function in temporal lobe epilepsy, its exact role is
unclear, as in vivo studies have suggested both pro- and anticonvulsant
properties. We have shown previously that SST has multiple inhibitory
cellular actions in the CA1 region of the hippocampus, suggesting that
in this region SST should have antiepileptic actions. To directly
assess the effect of SST on epileptiform activity, we studied two in
vitro models of epilepsy in the rat hippocampal slice preparation using
extracellular and intracellular recording techniques. In one,
GABA-mediated neurotransmission was inhibited by superfusion of the
GABAA receptor antagonist bicuculline. In the second, we
superfused Mg2+-free artificial cerebrospinal fluid to
remove the Mg2+ block of the
N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. We show here that SST markedly reduces the intensity of
evoked epileptiform afterdischarges and the frequency of spontaneous bursts in both CA1 and CA3. SST appears to act additively in the two
regions to suppress the transmission of epileptiform events through the
hippocampus. We further examined SST's actions in CA3 and found that
SST dramatically reduced the frequency of paroxysmal depolarizing
shifts (PDSs) recorded intracellularly in current clamp, as well as
increasing the threshold for evoking "giant" excitatory
postsynaptic currents (EPSCs), large polysynaptically mediated EPSCs
that are the voltage-clamp correlate of PDSs. We also examined the
actions of SST on pharmacologically isolated EPSCs generated at both
mossy fiber (MF) and associational/commissural (A/C) synapses. SST
appears to act specifically to reduce recurrent excitation between CA3
neurons because it depresses A/C- but not MF-evoked EPSCs. SST also
increased paired-pulse facilitation of A/C EPSCs, suggesting a
presynaptic site of action. Reciprocal activation of CA3 neurons
through A/C fibers is critical for generation of epileptiform activity
in hippocampus. Thus SST reduces feedforward excitation in rat
hippocampus, acting to "brake" hyperexcitation. This is a
function unique from that described for other hippocampal neuropeptides, which affect more standard neurotransmission. Our results suggest that SST receptors could be a unique, selective clinical target for treatment of limbic seizures.
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