Peptide-induced infant status epilepticus causes neuronal death and synaptic reorganization

Abstract

Status epilepticus (SE) produced by excitatory amino acids is a well established model in adult rodents. Limbic neuronal degeneration and synaptic reorganization observed after, for example, kainic acid-induced SE are considered relevant to human epilepsy. Kainic acid also produces severe seizures in infant rats, but neuronal injury and sprouting have not been demonstrated. The results of the present study show that corticotropin releasing hormone (CRH)-induced SE causes limbic neuronal death and reorganization in infant rats. In adults, CRH produced seizures at much higher doses, and no neuronal degeneration. As a modulator of the CNS stress response, CRH is activated in various 'stressful' circumstances. Its age-dependent ability to kill neurons represents a unique form of cell death potentially important in human medicine.

FIG. 1

Silver-stained coronal sections through limbic structures of rats subjected to i.c.v. CRH infusions on postnatal days 10–13. (A, B) Hippocampus. Low magnification (A), shows the pyramidal cell layers of CA1 and CA3 (arrow), as well as the granule cell layer (G) of the dentate gyrus. High magnification (B), reveals numerous degenerating neurons in CA3b (arrow). (C) Prominent silver staining in ipsilateral central amygdaloid nucleus (CAN). (D) No staining in the contralateral CAN (figure is photographically reversed for comparison purposes). (E) Dense silver deposits are visible in neurons of the superficial layers (arrow) of the piriform cortex (PC). Scale bar = 100 µm (B) or 200 µm (A, C, D, E).

FIG. 2

Light micrographs of Timm-stained mossy fiber sprouting in dentate gyrus of infant rats. (A) Kainic acid injection on postnatal day 12. No Timm staining in the inner molecular layer (IML) is visible. (B) Single CRH infusion on postnatal day 12. Modest sprouting (arrows), is visible as Timm-stained boutons in the IML. (C) Multiple CRH injections on postnatal days 10–13. Heavy mossy fiber sprouting (arrows) is visible in the IML. Magnification is the same for A,B,C: bar (in A) = 25 µm.