Biochemical and structural brain alterations in female mice with cerebral pyruvate dehydrogenase deficiency.

Pyruvate dehydrogenase complex (PDC) deficiency is an inborn metabolic disorder associated with a variety of neurologic abnormalities. This report describes the development and initial characterization of a novel murine model system in which PDC deficiency has been introduced specifically into the developing nervous system. The absence of liveborn male and a roughly 50% reduction in female offspring following induction of the X-linked mutation indicate that extensive deficiency of PDC in the nervous system leads to pre-natal lethality. Brain tissue from surviving females at post-natal days 15 and 35 was shown to have approximately 75% of wild-type PDC activity, suggesting that a threshold of enzyme activity exists for post-natal survival. Detailed histological analyses of brain tissue revealed structural defects such as disordered neuronal cytoarchitecture and neuropil fibers in grey matter, and reduced size of bundles and disorganization of fibers in white matter. Many of the histologic abnormalities resemble those found in human female patients who carry mutations in the X-linked ortholog. These findings demonstrate a requirement for PDC activity within the nervous system for survival in utero and suggest that impaired pyruvate metabolism in the developing brain can affect neuronal migration, axonal growth and cell-cell interactions.

Alcohol-induced neurodegeneration: when, where and why?

This manuscript reviews the proceedings of a symposium organized by Drs. Antonio Noronha and Fulton Crews presented at the 2003 Research Society on Alcoholism meeting. The purpose of the symposium was to examine recent findings on when alcohol induced brain damage occurs, e.g., during intoxication and/or during alcohol withdrawal. Further studies investigate specific brain regions (where) and the mechanisms (why) of alcoholic neurodegeneration. The presentations were (1) Characterization of Synaptic Loss in Cerebella of Mature and Senescent Rats after Lengthy Chronic Ethanol Consumption, (2) Ethanol Withdrawal Both Causes Neurotoxicity and Inhibits Neuronal Recovery Processes in Rat Organotypic Hippocampal Cultures, (3) Binge Drinking-Induced Brain Damage: Genetic and Age Related Effects, (4) Binge Ethanol-Induced Brain Damage: Involvement of Edema, Arachidonic Acid and Tissue Necrosis Factor alpha (TNFalpha), and (5) Cyclic AMP Cascade, Stem Cells and Ethanol. Taken together these studies suggest that alcoholic neurodegeneration occurs through multiple mechanisms and in multiple brain regions both during intoxication and withdrawal.

Disruption of frontocerebellar circuitry and function in alcoholism.

This article represents a symposium of the 2002 joint meeting of RSA and ISBRA held in San Francisco. Presentations were Neuropathology of alcohol-related cerebellar damage in humans, by Antony J. Harding; Neuropathological evidence of cerebellar damage in an animal model of alcoholism, by Roberta Pentney and Cynthia Dlugos; Understanding cortical-cerebellar circuits through neuroimaging study of chronic alcoholics, by Peter R. Martin and Mitchell H. Parks; and Functional reorganization of the brain in alcoholism: neuroimaging evidence, by John E. Desmond, S.H. Annabel Chen, Michelle R. Pryor, Eve De Rosa, Adolf Pfefferbaum, and Edith V. Sullivan.

Quantitative immunocytochemistry of GABA and synaptophysin in the cerebellar cortex of old ethanol-fed rats.

BACKGROUND: Ethanol-related synaptic loss, Purkinje neuron dendritic regression, and parallel fiber degeneration have been reported in the molecular layer of the adult cerebellar cortex. The known plasticity of the cerebellar cortex suggests that this region may respond to ethanol-related losses by compensatory remodeling of cerebellar circuitry. Stellate and basket interneurons may play an essential role in the remodeling process. Little is known about ethanol-related effects on cerebellar interneurons or on the GABAergic synapses that they form despite the fact that ethanol-related alterations in these components may contribute to the sensitivity of the cerebellum to ethanol. The paucity of data on GABAergic synapses extends to other synaptic components as well including synaptophysin, a glycoprotein component of synaptic vesicles and a synaptic marker. METHODS: Thirty 12-month-old F344 rats were divided into ethanol-fed, pair-fed, and chow-fed groups (10/group). Ethanol rats were treated for 40 weeks with a liquid diet in which 35% of the calories were derived from ethanol. At the end of treatment, rats were perfused, and tissue processed for quantitative immunohistochemistry of GABA and synaptophysin labels. RESULTS: Levels of GABA within inhibitory synapses formed by stellate and basket neurons and levels of synaptophysin were not altered by long-term ethanol treatment. CONCLUSIONS: Stable levels of GABA within GABAergic basket and stellate interneuron synapses suggest that interneurons in the molecular layer of the cerebellar cortex may not play a major role in remodeling of cerebellar circuitry following long-term ethanol consumption. The lack of ethanol-related alterations in synaptophysin levels reported here suggests that synaptic vesicles may be relatively insensitive to ethanol and that known ethanol-related effects on synapse number are due to other mechanisms.

The total numbers of cerebellar granule neurons in young and aged Fischer 344 and Wistar-Kyoto rats do not change as a result of lengthy ethanol treatment.

It is generally accepted that long term chronic ethanol consumption by young rats will lead to significant losses of cerebellar granule neurons (GN). A recent study in this laboratory showed, however, that 40 weeks of chronic ethanol consumption had no effect on the total numbers of GN in aged Fischer 344 rats (F344). The goals of the present study were to determine whether F344 GN were resistant to ethanol toxicity only in aged rats and whether resistance of GN in aged rats to ethanol toxicity occurred only in the F344 strain. To accomplish those goals, young and aged adult F344 and Wistar-Kyoto (WKY) rats were treated chronically with ethanol for 40 weeks during the first or second half of their life span. In each rat the total numbers of GN were estimated with the optical fractionator and the volumes of the GN layer were estimated according to Cavalieri's theorem. After the 40 weeks of ethanol, there were significant age-related differences in the total numbers of GN in the F344 rats. There were also significant strain-related differences in the total numbers of GN and volumes of the GN layer. There were no significant ethanol-related differences, however, in numbers of cerebellar GN or volumes of the GN layer in F344 rats or WKY rats. The results presented here show that consumption of ethanol over long periods of time had no effect on the total numbers of cerebellar GN or the granular layer volumes in young or aged F344 or WKY rats.