Abstracts

RATIONALE: Brief repeated noninjurious seizures evoked by minimal electroconvulsive shock (ECS) have been shown to decrease vulnerability to neuronal cell death in limbic system regions, while inducing sustained increases in the expression of nerve growth factor (NGF) in some of these same regions, including hippocampus and rhinal cortex. Thus, the induction of NGF is a potential mechanism for the neuroprotective action of ECS treatment. The activation of the tyrosine protein kinase activity of the TrkA receptor for NGF is a key mediator of the neuroprotective action of this neurotrophin. Thus, the purpose of this study was to determine whether ECS treatment causes an increase in TrkA protein expression and/or an increase in protein tyrosine phosphorylation. To determine the functional significance of changes in these parameters, we also compared the effects of a neuroprotective chronic ECS treatment with the effects of an acute ECS treatment that was not neuroprotective.
METHODS: Minimal ECS was administered via corneal electrodes (200 msec, 35 mA). A single ECS treatment session consisted of 3 ECS seizures, given at 30 min intervals (i.e. at 0, 30, and 60 min). Control (sham) animals received the same handling and contact with the electrodes, but no current was passed. Animals were behaviorally observed to ensure that minimal limbic motor seizures (clonic movements of the face and forelimbs) lasting 5-10 sec occurred after each ECS. Acute treatment consisted of a single ECS treatment session. Chronic ECS consisted of daily treatment (one session per day given in the morning) for 7 days. TrkA and tyrosine phosphorylation were measured immunohistochemically using specific antibodies.
RESULTS: In rats treated with chronic ECS, upregulation of TrkA receptors was found in rhinal cortex and in several hippocampal areas (CA1, CA2, CA3 and polymorph layer dentate gyrus) by 4-7 hr. This increased expression of TrkA was still observed in CA2 and CA3 at 24 hours after the last seizure. Moreover, these same rats also showed upregulation of TrkA in the anterior olfactory nucleus (medial part) after 4,6,7 and 24 hr after the last seizure. Acutely treated rats exhibited a transient increase in TrkA expression that was present in rhinal cortex and hippocampus only during the first 7 hr. In addition, upregulation in TrkA immunoreactivity was co-localized with increased tyrosine phosphorylation levels.
CONCLUSIONS: Our results demonstrate that chronic ECS causes a sustained upregulation of TrkA expression and tyrosine phosphorylation in several limbic areas in which neuroprotective effects are observed. These results are consistent with the hypothesis that NGF contributes to ECS-evoked neuroprotection.