Mechanisms of ethanol-induced degeneration in the developing, mature, and aging cerebellum

Medical School and Tampere University Hospital, Department of Internal Medicine, University of Tampere, Tampere, Finland.
The Cerebellum (Impact Factor: 2.72). 05/2008; 7(3):332-47. DOI: 10.1007/s12311-008-0034-z
Source: PubMed


The adverse effects of acute and chronic ethanol exposure on cerebellar functions have been acknowledged for decades, in terms of impaired control of movement and balance. In addition to the motor impairment, cerebellar degeneration has recently been shown to contribute to distinct neuropsychological deficits in chronic alcoholics, as well as in children with prenatal ethanol exposure. The basic mechanisms underlying these ethanol-induced functional alterations and the related neuropathology in the cerebellum have mostly been clarified only recently. These mechanisms include: (i) excitotoxicity; (ii) dietary factors, especially thiamine depletion; (iii) glial abnormalities; (iv) changes in growth factors; (v) apoptotic mechanisms; (vi) oxidative stress; and (vii) compromised energy production. Although these mechanisms widely apply not only to the mature cerebellum, but also to the developing and the aging cerebella, the developing and the aged cerebellum have some special characteristics, which may make them even more vulnerable to ethanol-induced degeneration. These special instances will be discussed along with the general mechanisms of ethanol-induced cerebellar degeneration.

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    • "FASDs are among the most common neurodevelopmental disorders, affecting up to 5% of the population in the United States and Western Europe (May et al., 2009). Individuals with FASDs often exhibit impairments in balance , delays in gross and fine motor skills (Jaatinen and Rintala, 2008; Mattson and Riley, 1998; Nguyen et al., 2012), and deficits in motor learning (i.e., cerebellar-mediated eyeblink conditioning (Jacobson et al., 2011, 2008)), and additional cognitive deficits that could also be related to cerebellar damage, such as: impaired math skills (Lebel et al., 2010) and dyslexia (Coffin et al., 2005). A reduction in cerebellar volume and white matter tracts have been "
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    ABSTRACT: Exposure to ethanol (EtOH) during fetal development can lead to long-lasting alterations, including deficits in fine motor skills and motor learning. Studies suggest that these are, in part, a consequence of cerebellar damage. Cerebellar granule neurons (CGNs) are the gateway of information into the cerebellar cortex. Functionally, CGNs are heavily regulated by phasic and tonic GABAergic inhibition from Golgi cell interneurons; however, the effect of EtOH exposure on the development of GABAergic transmission in immature CGNs has not been investigated. To model EtOH exposure during the 3(rd) trimester-equivalent of human pregnancy, neonatal pups were exposed intermittently to high levels of vaporized EtOH from postnatal day (P) 2 to P12. This exposure gradually increased pup serum EtOH concentrations (SECs) to ∼60 mM (∼0.28 g/dl) during the 4 hours of exposure. EtOH levels gradually decreased to baseline 8 hrs after the end of exposure. Surprisingly, basal tonic and phasic GABAergic currents in CGNs were not significantly affected by postnatal alcohol exposure (PAE). However, PAE increased the expression of δ subunit expression at P28 as detected by immunohistochemical and western blot analyses. Also, electrophysiological studies with an agonist that is highly selective for δ-containing GABAA receptors, 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol (THIP), showed an increase in THIP-induced tonic current. Behavioral studies of PAE rats did not reveal any deficits in motor coordination, except for a delay in the acquisition of the mid-air righting reflex that was apparent at P15 to P18. These findings demonstrate that repeated intermittent exposure to high levels of EtOH during the equivalent of the last trimester of human pregnancy has significant but relatively subtle effects on motor coordination and GABAergic transmission in CGNs in rats.
    Neuropharmacology 12/2013; 79. DOI:10.1016/j.neuropharm.2013.11.020 · 5.11 Impact Factor
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    • "Chronic ethanol abuse/dependence leads to disruption of white matter in general (Pfefferbaum et al., 2006c), with consistent findings of disruption found in the corpus callosum (Kashem et al., 2008, 2009; Pfefferbaum and Sullivan, 2005; Pfefferbaum et al., 2006b) and frontal cortex (Harris et al., 2008; Liu et al., 2006, 2007; Mayfield et al., 2002; Sullivan, 2003). Chronic ethanol abuse induces profound degeneration in the cerebellum as well (Fitzpatrick et al., 2008; Jaatinen and Rintala, 2008; Sullivan, 2003). Peri-adolescent brain development is particularly sensitive to the deleterious effects of ethanol, with evidence indicating that ethanol-induced alterations in and/or disruptions of this development predisposes an individual to continued ethanol use and abuse as well as subsequent dependence (Clark et al., 2008; Crews et al., 2007; Spear, 2000, 2004a, 2007; Witt, 2010). "
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    ABSTRACT: Adolescent alcohol abuse remains a serious public health concern, with nearly a third of high school seniors reporting heavy drinking in the previous month. Using the high ethanol-consuming C57BL/6J mouse strain, we examined the effects of ethanol (3.75 g/kg, IP, daily for 45 days) on body weight and brain region mass (cerebral cortex, cerebellum, corpus callosum) during peri-adolescence (postnatal day [P]25 to 70) or adulthood (P180 to 225) of both males and females. In control peri-adolescent animals, body weight gain was greater in males compared with females. In the peri-adolescent exposure group, ethanol significantly reduced body weight gain to a similar extent in both male and female mice (82 and 84% of controls, respectively). In adult animals, body weight gain was much less than that of the peri-adolescent mice, with ethanol having a small but significant effect in males but not females. Between the control peri-adolescent and adult cohorts (measurements taken at P70 and 225, respectively), there were no significant differences in the mass of the cerebral cortex or the cerebellum from either male or female mice, although the rostro-caudal length of the corpus callosum increased slightly but significantly (6.1%) between these time points. Ethanol treatment significantly reduced the mass of the cerebral cortex in peri-adolescent (-3.1%), but not adult, treated mice. By contrast, ethanol significantly reduced the length of the corpus callosum in adult (-5.4%), but not peri-adolescent, treated mice. Future studies at the histological level may yield additional details concerning ethanol and the peri-adolescent brain.
    Alcoholism Clinical and Experimental Research 03/2012; 36(10):1728-37. DOI:10.1111/j.1530-0277.2012.01759.x · 3.21 Impact Factor
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    • "Lesion studies (Victor et al. 1989) and behavioral and brain imaging (Rosenbloom et al. 2007; Sullivan et al. 2006) have demonstrated a strong association between cerebellar atrophy and impaired gait and balance, marked by lower limb ataxia. Ethanol-induced cerebellar damage may be caused by excitotoxicity, dietary factors (particularly thiamine depletion), glial abnormalities, oxidative stress, and impaired energy production (Baker et al. 1999; Jaatinen and Rintala 2008). "
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    ABSTRACT: Disturbed gait and balance are among the most consistent sequelae of chronic alcoholism. However, although a majority of alcoholics have never sought treatment, most investigations showing ataxia in alcohol-dependent individuals have relied on samples drawn from treated populations. In addition, few studies have addressed the associations of codependence on other drugs with alcoholic gait and balance disturbance. This study employed the Walk-a-Line Ataxia Battery (Fregly et al. Alcohol Clin Exp Res 1972;43:395-399) to assess gait and balance in treatment-naïve, actively drinking alcohol-dependent men and women (TNA; n = 69) who were dependent on alcohol only (ALC; n = 43), or who also had a lifetime drug dependence (ALC + DRG; n = 26; i.e., methamphetamine, cocaine, opiates, and/or marijuana), compared with nonsubstance abusing controls (NSAC; n = 74).We also examined associations between lifetime alcohol use and age with gait and balance measures. Our main findings were (i) no evidence of disturbed gait and balance in ALC versus NSAC and (ii) significantly disturbed gait and balance in ALC + DRG, relative to both NSAC and ALC, along with steeper age-associated decline in gait and balance performance in ALC versus ALC + DRG. Our results provide evidence consistent with previous studies that TNA (without a lifetime drug codependence) may represent a population that is different and less impaired (including in gait and balance) than treated alcoholics. Additionally, we provide evidence that ALC + DRG, with greater alcohol use and family drinking density than ALC, have an accelerated effect of age on gait and balance disturbance compared with both NSAC and ALC. The ALC + DRG group likely represents a subset of TNA with different characteristics than ALC.
    Alcoholism Clinical and Experimental Research 03/2012; 36(9):1550-62. DOI:10.1111/j.1530-0277.2012.01772.x · 3.21 Impact Factor
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