The tumor suppressor gene p53 recently has been associated with the induction of cell death in response to some forms of cellular damage. A possible role for p53-related modulation of neuronal viability has been suggested by the finding that p53 expression is increased in damaged neurons in models of ischemia and epilepsy. We evaluated the possibility that p53 expression (in knockout mice) is required for induction of cell damage in a model of seizure activity normally associated with well defined patterns of cell loss. Subcutaneous injection of kainic acid, a potent excitotoxin, induced comparable seizures in both wild-type mice (+/+) and mice deficient in p53 (-/-). Using a silver impregnation technique to examine neurodegeneration in animals killed 7 d after kainate injection, we found that a majority of +/+ mice exhibited extensive cell loss in the hippocampus, involving subregions CA1, CA3, the hilus, and the subiculum. Apoptotic cell death, as identified with an in situ nick end labeling technique to detect DNA fragmentation, was confirmed in CA1- but not CA3-degenerating neurons. In marked contrast, a majority of p53 -/- mice displayed no signs of cell damage; in the remaining p53 -/- mice, damage was mild to moderate and was confined almost entirely to cells in CA3b of the dorsal hippocampus. In +/+ mice, but not in -/- mice, damaged neurons also were observed in the amygdala, piriform cortex, cerebral cortex, caudate-putamen, and thalamus after kainate treatment. The pattern and extent of damage in mice heterozygous for p53 (+/-) were identical to those seen in +/+ mice, suggesting that a single copy of p53 is sufficient to confer neuronal vulnerability. These results demonstrate that p53 influences viability in multiple neuronal subtypes and brain regions after excitotoxic insult.

Intracellular recordings were obtained in the vitro slice preparation from neurons of lateral and mesial temporal cortex removed from human epileptics suffering from intractable temporal lobe seizures. Spontaneous rhythmic synaptic events, which were capable of triggering action potential discharge, were observed in many neurons, particularly in mesial tissue slices. Such activity may reflect the epileptogenic capacity of this human cortex.

Immunocytochemical techniques were used to examine the synaptic relations of inhibitory interneurons in the developing rabbit hippocampus. Glutamic acid decarboxylase (GAD), the synthesizing enzyme for the inhibitory neurotransmitter GABA, was found in interneurons of immature (8 d old) as well as mature (30 d old) tissue. GAD-immunoreactivity was seen in somata, dendrites, and axon terminals of interneurons at both ages. Electron-microscopic examination revealed that GAD-positive "terminals" in immature tissue were often not associated with the usual synaptic specializations, but were rather in simple apposition to the "postsynaptic" element. In mature tissue, GAD-positive terminals made symmetric contacts primarily with pyramidal cell somata, initial segments, and proximal dendrites. In addition, GAD-positive terminals synapsed onto both GAD-positive and GAD-negative interneuron profiles.