Pyramidal neurons in the CAI field of the hippocampus die a few days after transient cerebral ischemia.4,21 Excessive excitatory synaptic activation following reperfusion is thought to be responsible for such de-layed cell death. 4,24 However, it remains controversial whether excitatory synaptic transmission in the CAI field is increased following reperfusion.2'3'1'1u18'26 Here we report a novel postsynaptic potential evoked from CAI pyramidal neurons preceding cell death after transient forebrain ischemia with intracellular record-ing and staining techniques in vivo. This result indicates the dramatic alteration of synaptic transmission in CAI neurons after transient ischemia. The ischemia-induced postsynaptic potential may be associated with the postischemic neuronal injury. Copyright

Hypoxia is a major cause of neonatal encephalopathy and seizures, and an increased neuronal excitability may be an underlying mechanism. To determine the role of Ca2+-activated K+ channels in hyperexcitability, we measured large unitary conductance (>200 pS, BKca) currents in symmetrical 140/140 mM K+ using inside-out configuration in CA1 pyramidal cells acutely dissociated from the hippocampus of rats exposed to normoxia or hypoxia (at 10% inspired 02) for 4 weeks after birth. About 53% of the patches contained BKca channels in the normoxic group, but only 20% in the hypoxic one. There were no differences in channel conductance or reversal potential between the groups. Yet, the open probability of BKca channels was much less in hypoxic neurons than that in the control, because of a decrease in channel open time and a prolongation of the closed time. These were partially recovered by an oxidizing but not by reducing agent, suggesting an involvement of redox mechanism. Results indicate that the Ca2+-activated K+ channel activities in hippocampal CA1 neurons are modulated by hypoxia during maturation. The reduction in BKca activity may contribute to hypoxia-induced neuronal hyperexcitability.

It has been recently reported that potassium channel increases activities in CA1 pyramidal neurons of rat hippocampus following transient forebrain ischemia. To understand the role of the enhanced potassium current in the pathogenesis of neuronal damage after ischemia, we examined the effects of tetraethylammonium (TEA) and 4-aminopyridine (4-AP) on the neuronal injury of CA1 region induced by 15 min forebrain ischemia using a four-vessel occlusion model. Adult rats received intracerebroventricular administration of either TEA or 4-AP after ischemia or TEA before ischemia and once each day for 7 days. In the postischemic TEA treated-rats, the neuronal injury in hippocampal CA1 region was signifi-cantly less than that of the controls. In contrast, neither preischemic infusion of TEA nor postischemic treatment of 4-AP had any neuroprotective effects. The present study demonstrates that postischemic application of TEA protects hippo-campal CA1 pyramidal neurons against ischemic insult, suggesting that potassium channels may play important roles in the pathogenesis of CA1 neuronal death after transient forebrain ischemia.

Redox regulation of BKca channels was studied in CA1 pyramidal neurons of adult rat hippocampus by using inside-out configuration of patch clamp. Intracellular application of oxidizing agent 5, 5-dithio-bis (2-nitrobenzoic acid)(DTNB) markedly increased activity of BKca channels and this stimulating action persisted even after washout. In contrast, the reducing agent dithiothreitol (DTT) had no apparent effects on channel activity but could reverse the pre-exposure of DTNB-induced enhancement. The increase in channel activity produced by DTNB was due to shortened closed time as well as prolonged open time. The effects exerted by another redox couple glutathione disulphide and its reducing form were similar as DTNB and DTT. The present results indicate that BKca channels in CA1 pyramidal neurons can be modulated by intracellular redox potential, and that augmentation of BKca channels by oxidative stress might contribute to the postischemic electrophysiological alterations of CA1 pyramidal neurons.