Functional and morphological changes induced by transient in vivo ischemia

Brief transient ischemia causes a delayed neuronal death of pyramidal neurons in the CA1 area of hippocampus after a period of hyperexcitability. We have previously shown that the hyperexcitability is due to an increase in an N-methyl-D-aspartate (NMDA) component of the response. In the present study, we recorded intracellularly from pyramidal neurons in CAI and find that there is little change in membrane potential or input resistance at this point in time. The dramatic increase in the NMDA component of the synaptic response is a result of a significant reduction in the ability of Mg²⁺ to induce a normal voltage-dependent blockade of the response. In spite of the relatively normal membrane properties, there is at this time a significant reduction in the amplitude of the population excitatory potential and a near total loss of longterm potentiation. In contrast, post-tetanic potentiation is unchanged in magnitude and character. These observations suggest more severe damage to the neuron than indicated by the membrane potential and resistance. When single neurons were injected with horseradish peroxidase and visualized after the electrophysiological recording, we found extensive beading of the dendrites in both the apical and basal regions, presumably reflecting a disproportionate damage to the dendritic areas, which are the primary sites of the excitatory amino acid synapses onto the neuron. These observations are consistent with the hypothesis that transient ischemia causes a fundamental change in the NMDA-activated ion channel such that Mg²⁺ is no longer able to block the response, resulting in increased entry of calcium into synaptic regions, which causes dendritic damage that progresses to neuronal cell death.