CORTICOSTERONE EXACERBATES KAINATE-INDUCED ALTERATIONS IN HIPPOCAMPALTAU IMMUNOREACTIVITY AND SPECTRIN PROTEOLYSIS INVIVO

Aberrant elevations in intracellular calcium levels, promoted by the e xcitatory amino acid glutamate, may be a final common mediator of the neuronal damage that occurs in hypoxic-ischemic and seizure disorders. Glutamate and altered neuronal calcium homeostasis have also been pro posed to play roles in more chronic neurodegenerative disorders, inclu ding Alzheimer's disease. Any extrinsic factors that may augment calci um levels during such disorders may significantly exacerbate the resul ting damage. Glucocorticoids (GCs), the adrenal steroid hormones relea sed during stress, may represent one such extrinsic factor. GCs can ex acerbate hippocampal damage induced by excitotoxic seizures and hypoxi a-ischemia, and we have observed recently that GCs elevate intracellul ar calcium levels in hippocampal neurons. We now report that the excit otoxin kainic acid (KA) can elicit antigenic changes in the microtubul e-associated protein tau similar to those seen in the neurofibrillary tangles of Alzheimer's disease. KA induced a transient increase in the immunoreactivity of hippocampal CA3 neurons towards antibodies that r ecognize aberrant forms of tau (5E2 and Alz-50). The tau immunoreactiv ity appeared within 3 h of KA injection, preceded extensive neuronal d amage, and subsequently disappeared as neurons degenerated. KA also ca used spectrin breakdown, indicating the involvement of calcium-depende nt proteases. Physiological concentrations of corticosterone (the spec ies-typical GC of rats) enhanced the neuronal damage induced by KA and , critically, enhanced the intensity of tau immunoreactivity and spect rin breakdown. Moreover, the GC enhancement of spectrin proteolysis wa s prevented by energy supplementation, supporting the hypothesis that GC disruption of calcium homeostasis in the hippocampus is energetic i n nature. Taken together, these findings demonstrate that neurofibrill ary tangle-like alterations in tau, and spectrin breakdown, can be ind uced by excitatory amino acids and exacerbated by GCs in vivo.