Contribution ofIhand GABABto Synaptically Induced Afterhyperpolarizations in CA1: A Brake on the NMDA Response

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Abstract
CA1 pyramidal cells receive two major excitatory inputs: the perforant path (PP) terminates in the most distal dendrites, whereas the Schaffer collaterals (SC) terminate more proximally. We have examined the mechanism of the afterhyperpolarization (AHP) that follows single subthreshold excitatory postsynaptic potentials (EPSPs) in these inputs. The AHPs were not reduced by a GABAAantagonist or by agents that block Ca2+entry. Application of the Ihblocker, ZD7288, partially blocked the AHP in the PP; the substantial remaining component was blocked by 2-hydroxysaclofen, a GABABantagonist. In contrast, the AHP in the SC depends nearly completely on Ih, with almost no GABABcomponent. Thus postsynaptic GABABreceptors appear to be preferentially involved at distal synapses, consistent with the spatial distribution of GABABreceptors and g protein-coupled inward rectifying potassium (GIRK) channels. GABABdoes, however, play a role at proximal synapses through presynaptic suppression of glutamate release, a mechanism that is much weaker at distal synapses. Experiments were conducted to explore the functional role of the AHP in the PP, which has a higher N-methyl-d-aspartate (NMDA)/AMPA ratio than the SC. Blockade of the AHP converted a response that had a small NMDA component to one that had a large component. These results indicate that the Ihand postsynaptic GABABconductances act as a brake on distally generated NMDA responses.