Contribution of Ih and GABAB to synaptically induced afterhyperpolarizations in CA1: a brake on the NMDA response.

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 GABAA antagonist or by agents that block Ca2+ entry. Application of the Ih blocker, ZD7288, partially blocked the AHP in the PP; the substantial remaining component was blocked by 2-hydroxysaclofen, a GABAB antagonist. In contrast, the AHP in the SC depends nearly completely on Ih, with almost no GABAB component. Thus postsynaptic GABAB receptors appear to be preferentially involved at distal synapses, consistent with the spatial distribution of GABAB receptors and g protein-coupled inward rectifying potassium (GIRK) channels. GABAB does, 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 Ih and postsynaptic GABAB conductances act as a brake on distally generated NMDA responses.