Electron microscopic analysis of adrenalectomy-induced hippocampal granule cell degeneration in the rat: apoptosis in the adult central nervous system.

As described in the preceding paper, adrenalectomy triggers hippocampal granule cell degeneration that begins within days after adrenalectomy, continues for months, and is the only apparent cell death anywhere within the brain. At the light microscopic level, granule cell degeneration is characterized by coalescing of nuclear chromatin into numerous spherical bodies. Since the morphology at the light microscopic level resembled the nuclear morphology characteristic of "apoptosis" rather than "necrosis," we undertook this ultrastructural study to determine if adrenalectomy induces the morphological features characteristic of apoptosis. Electron microscopy revealed coalescing of nuclear chromatin, compaction of cytoplasm, and the budding-off of cytoplasmic bodies that were engulfed by glia. Mitochondria, the Golgi apparatus, and rough endoplasmic reticulum appeared relatively normal early in the process of granule cell degeneration when nuclear changes were prominent. Presynaptic terminals innervating degenerating granule cells appeared normal. Electron-dense degeneration of granule cell axon terminals in association with normal postsynaptic elements of CA3 pyramidal cells highlighted the extraordinary selectivity of adrenalectomy-induced granule cell death. Ten weeks after adrenalectomy, astrocytes were filled with abnormally abundant glial fibrils and neuronal debris. This "apoptotic" morphology produced by adrenalectomy was clearly distinct from the "necrotic" granule cell morphology produced by intrahippocampal injection of the neurotoxin volkensin. These results indicate that, in a manner possibly analogous to castration-induced prostate cell death, loss of adrenal hormone triggers a process in dentate granule cells that causes the morphological changes characteristic of "apoptosis." Thus, adrenal steroids may be obligatory growth factors for dentate granule cells and their loss may initiate a selective process in the mature brain that is unique or that may normally occur only in the developing brain.