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Purkinje cell-specific deletion of CREB worsens alcohol-induced cerebellar neuronal losses and motor deficits
Journal article   Open access   Peer reviewed

Purkinje cell-specific deletion of CREB worsens alcohol-induced cerebellar neuronal losses and motor deficits

Dylan Todd, Michael Clapp, Parker Dains, Bahri Karacay and Daniel J Bonthius
Alcohol (Fayetteville, N.Y.), Vol.101, pp.27-35
04/01/2022
DOI: 10.1016/j.alcohol.2022.02.005
PMCID: PMC9783827
PMID: 35378204
url
https://www.ncbi.nlm.nih.gov/pmc/articles/9783827View
Open Access

Abstract

Exposure to alcohol during pregnancy can kill developing fetal neurons and lead to FASD in the offspring. However, not all fetuses are equally vulnerable to alcohol toxicity. These differences in vulnerability among individuals are likely due, at least in part, to genetic differences. Some genes encode neuroprotective molecules that act through signaling pathways to protect neurons against alcohol’s toxic effects. One signaling pathway that can protect cultured neurons against alcohol-induced cell death in vitro is the cAMP pathway. A goal of this study was to determine whether the cAMP pathway can exert a similar neuroprotective effect against alcohol in vivo. A key molecule within the cAMP pathway is CREB. In this study, CREB was specifically disrupted in cerebellar Purkinje cells to study its role in protection of cerebellar neurons against alcohol toxicity. Mice with Purkinje cell-specific knockout of CREB were generated with the Cre-lox system. A 2x2 design was used in which Cre-negative and Cre-positive mice received either 0.0 or 2.2 mg/g EtOH by IP injection daily over PD 4-9. Stereological cell counts of cerebellar Purkinje cells and granule cells were performed on PD 10. Motor function was assessed on PD 40 using the rotarod. Purkinje cell-specific disruption of CREB alone (in the absence of alcohol) induced only a small reduction in Purkinje cell number. However, the loss of CREB function from Purkinje cells greatly increased the vulnerability of Purkinje cells to alcohol-induced cell death. While alcohol killed 20% of Purkinje cells in the Cre-negative (CREB-expressing) mice, alcohol killed 57% of Purkinje cells in the Cre-positive (CREB-nonexpressing) mice. This large loss of Purkinje cells did not lead to similar alcohol-induced losses of granule cells. In the absence of alcohol, lack of CREB function in Purkinje cells had no effect on rotarod performance. However, in the presence of alcohol, disruption of CREB in Purkinje cells substantially worsened rotarod performance. Disruption of a single gene (CREB) in a single neuronal population (Purkinje cells) greatly increases the vulnerability of that cell population to alcohol-induced cell death and worsens alcohol-induced brain dysfunction. The results suggest that the cAMP pathway can protect cells in vivo against alcohol toxicity and underline the importance of genetics in determining the neuropathology and behavioral deficits of FASD. •Purkinje cell-specific deletion of CREB modestly reduces Purkinje cell number.•Targeted deletion of CREB substantially worsens alcohol-induced Purkinje cell loss in the developing mouse.•The increased loss of Purkinje cells from the combination of CREB deletion and alcohol exposure does not lead to an increased loss of granule cells.•Purkinje cell-specific deletion of CREB worsens the motor deficits caused by developmental alcohol exposure.•A gene variant, isolated to a single neuronal cell type, can lead to substantial differences in alcohol-induced behavioral deficits.
 Fetal Alcohol Syndrome Genetics cAMP rotarod

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