Ethanol-Induced Alterations in Purkinje Neuron Dendrites in Adult and Aging Rats: a Review

Abstract

Uncomplicated alcoholics suffer from discrete motor dysfunctions that become more pronounced with age. These deficits involve the structure and function of Purkinje neurons (PN), the sole output neurons from the cerebellar cortex. This review focuses on alterations to the PN dendritic arbor in the adult and aging Fischer 344 rat following lengthy alcohol consumption. It describes seminal studies using the Golgi-Cox method which proposed a model for ethanol-induced dendritic regression. Subsequent ultrastructural studies of PN dendrites showed dilation of the extensive smooth endoplasmic reticulum (SER) which preceded and accompanied dendritic regression. The component of the SER that was most affected by ethanol was the sarco/endoplasmic reticulum Ca(2+) ATPase pump (SERCA) responsible for resequestration of calcium into the SER. Ethanol-induced decreases in SERCA pump levels, similar to the finding of SER dilation, preceded and occurred concomitantly with dendritic regression. Discrete ethanol-induced deficits in balance also accompanied these decreases. Ethanol-induced ER stress within the SER of PN dendrites was proposed as an underlying cause of dendritic regression. It was recently shown that increased activation of caspase 12, inherent to the ER, occurred in PN of acute slices in ethanol-fed rats and was most pronounced following 40 weeks of ethanol treatment. These findings shed new light into alcohol-induced disruption in PN dendrites providing a new model for the discrete but critical changes in motor function in aging, adult alcoholics.

An Overview of the Role of Lipofuscin in Age-Related Neurodegeneration

“…Also in a murine model, it was observed that chronic sleep disruption resulted in frequent activation of wake-activated neurons (WAN), which promotes mitochondrial metabolic stress and increased LF accumulation in a subgroup of WAN (Zhu et al, 2015 ). On the other hand, chronic alcohol consumption induces increasing LF deposition in rat hippocampal neurons (Borges et al, 1986 ) and Purkinje (Lewandowska et al, 1994 ; Wenisch et al, 1997 ; Dlugos, 2015 ). Mice lacking the expression of glycerophosphodiester phosphodiesterase 2 (a six-transmembrane protein that cleaves glycosylphosphatidylinositol anchors) show early neurodegeneration with vacuolization, microgliosis, cytoskeletal accumulation, and LF deposition followed by astrogliosis and cell death (Cave et al, 2017 ).…”

Mechanisms of Ethanol-Induced Cerebellar Ataxia: Underpinnings of Neuronal Death in the Cerebellum

“…Recent animal experiments have demonstrated that ethanol can directly cause cerebellar degeneration and that such an effect is potentiated by aging [52]. Chronic exposure to alcohol induces oxidative stress through a multitude of sources.…”

Advances and New Concepts in Alcohol-Induced Organelle Stress, Unfolded Protein Responses and Organ Damage

“…The expression of the ER-resident HSP47 can be induced by the Golgi stress, which protects cells from Golgi stress-induced apoptosis [ 90 ]. In addition, it is known that acute or chronic alcohol inhibits the ER resident SERCA in human and mouse hepatocytes [ 55 ] and in neurons of mouse spinal cord and rat Purkinje [ 131 ]. Since there is a SERCA-mediated intricate relationship between the ER and mitochondria in intracellular calcium homeostasis [ 131 ], the alcoholic inhibition of SERCA could accommodate a massive transfer of calcium from the ER to mitochondria resulting in worsened ER stress-caused cell death [ 132 ].…”