Ethanol exposure during development reduces GABAergic/glycinergic neuron numbers and lobule volumes in the mouse cerebellar vermis

Abstract

Cerebellar alterations are a hallmark of Fetal Alcohol Spectrum Disorders and are thought to be responsible for deficits in fine motor control, motor learning, balance, and higher cognitive functions. These deficits are, in part, a consequence of dysfunction of cerebellar circuits. Although the effect of developmental ethanol exposure on Purkinje and granule cells has been previously characterized, its actions on other cerebellar neuronal populations are not fully understood. Here, we assessed the impact of repeated ethanol exposure on the number of inhibitory neurons in the cerebellar vermis. We exposed pregnant mice to ethanol in vapor inhalation chambers during gestational days 12–19 and offspring during postnatal days 2–9. We used transgenic mice expressing the fluorescent protein, Venus, in GABAergic/glycinergic neurons. Using unbiased stereology techniques, we detected a reduction in Venus positive neurons in the molecular and granule cell layers of lobule II in the ethanol exposed group at postnatal day 16. In contrast, ethanol produced a more widespread reduction in Purkinje cell numbers that involved lobules II, IV–V and IX. We also found a reduction in the volume of lobules II, IV–V, VI–VII, IX and X in ethanol-exposed pups. These findings indicate that second and third trimester ethanol exposure has a greater impact on Purkinje cells than interneurons in the developing cerebellar vermis. The decrease in the volume of most lobules could be a consequence of a reduction in cell numbers, dendritic arborizations, or axonal projections.

Effects of prenatal alcohol exposure (PAE): insights into FASD using mouse models of PAE

“…Moreover, PAE mice had an increased latency to fall in rotarod testing, supporting the data indicating that ataxia and motor learning impairments are primarily caused by increased Punkinje cell firing rates (Servais et al 2007). An inhalation based, chronic GD12–19 and PN2–9 exposure paradigm, modeling high (4.5 g/dL) BAC, demonstrated reductions in cerebellar Purkinje cells in lobules II, IV, V, and IX, with reductions in GABAergic cells only in lobule II (Nirgudkar et al 2016). Furthermore, PAE mice exhibited a reduction in cerebellar volume, specifically in lobules II, IV, V, VI, VII, IX, and X, suggesting that cerebellar Punkinje cells are more sensitive to alcohol than GABAergic cells (Nirgudkar et al 2016).…”

“…An inhalation based, chronic GD12–19 and PN2–9 exposure paradigm, modeling high (4.5 g/dL) BAC, demonstrated reductions in cerebellar Purkinje cells in lobules II, IV, V, and IX, with reductions in GABAergic cells only in lobule II (Nirgudkar et al 2016). Furthermore, PAE mice exhibited a reduction in cerebellar volume, specifically in lobules II, IV, V, VI, VII, IX, and X, suggesting that cerebellar Punkinje cells are more sensitive to alcohol than GABAergic cells (Nirgudkar et al 2016). Conversely, Cuzon et al used 2% ( w / v ) alcohol in an ad libitum drinking model, with exposure from GD0 to 14.5, as a chronic low BAC model.…”

Murine Models for the Study of Fetal Alcohol Spectrum Disorders: An Overview

“…First trimester equivalent: cranial dysmorphologies ( 60 , 61 ), brain malformations ( 61 , 62 ) and altered gray and white matter tracts ( 63 ). Second trimester equivalent: craniofacial and brain malformations ( 62 , 64 , 65 ), neurodevelopmental disorders ( 66 , 67 ) and fetal growth restriction ( 68 , 69 ). Third trimester equivalent: brain abnormalities ( 70 – 72 ), neurodevelopmental disorders ( 71 , 73 ).…”

Simultaneous MEG/EEG recordings for the study of source domain brain connectivity in neurodegenerative diseases

“…Alcohol consumption is also known to produce neurodegeneration in prefrontal areas (Zahr and Pfefferbaum, 2017). This neurodegeneration has been observed to affect inhibitory GABAergic interneuron in fetal alcohol spectrum disorder models in mice (Smiley et al, 2015;Nirgudkar et al, 2016;Hamilton et al, 2017). A similar mechanism could cause RDS-like symptomatology in adults.…”