The purpose of the proposed experiments is to examine the neurotoxic effects of the HIV envelope glycoprotein (gp120) on specific neuronal populations of the hippocampal formation and to relate those effects to changes in the neuronal circuitry which could constitute the neuroanatomic substrate for HIV-associated seizures. In naturally- occurring human temporal lobe epilepsy and the kainate-treated rat model of this disorder, a characteristic loss of denate hilar cells occurs concomitant with sprouting of the axons of dentate granule cells. This alteration in the connectivity of cellular populations in the hippocampal formation may represent the basis for recurrent seizures in both epilepsy and HIV. The hypotheses to be tested in the proposed research are that hilar mossy cells and somatostatin-positive cells are vulnerable to the neurotoxic effects of HIV gp120 and that granule cells are less susceptible to these effects and can elaborate additional axonal projections in the face of exposure to HIV-associated neurotoxins. To test these hypotheses, organotypic cultures of the hippocampal formation will be exposed to gp120. Semi-thin sections of the treated cultures will be stained by immunohistochemistry, and cell counts made to identify specific cellular types vulnerable to the neurotoxic effects of gp120. A specific axon label for granule cells (Timm stain) will be used to demonstrate the development of axonal sprouting. The proposed research will make use of an in vitro culture system which preserves cellular relationships which may be crucial to the manifestation of the toxic effects of gp120. The results of these experiments will advance the understanding of the neuroanatomic substrate of seizures in HIV infection.
