Abstract
To better understand the cellular pathogenetic mechanisms of fetal alcohol spectrum disorder (FASD) and the therapeutic benefit of stem cell treatment, we exposed pregnant rats to ethanol followed by intravenous administration of neural stem cells (NSCs) complexed with atelocollagen to the new born rats and studied recovery of GABAergic interneuron numbers and synaptic protein density in the anterior cingulate cortex, hippocampus and amygdala. Prenatal ethanol exposure reduced both parvalbumin-positive phenotype of GABAergic interneurons and postsynaptic density protein 95 levels in these areas. Intravenous NSC treatment reversed these reductions. Furthermore, treatment with NSCs reversed impaired memory/cognitive function and social interaction behavior. These experiments underscore an important role for synaptic remodeling and GABAergic interneuron genesis in the pathophysiology and treatment of FASD and highlight the therapeutic potential for intravenous NSC administration in FASD utilizing atelocollagen.
Highlights
Prenatal alcohol exposure is invariably detrimental to the developing central nervous system and can cause behavioral/ cognitive and mental/social problems, defined as fetal alcohol spectrum disorders (FASDs).[1,2] Abnormalities in cortical and limbic system development have been linked to FASD, but the underlying cellular pathogenesis in the brain remains elusive
We studied the involvement of corticolimbic GABAergic interneuron disruption in cognitive and social impairment in FASD and the effect of stem cell treatment
We show that alterations of PVcontaining GABAergic interneurons and synaptic density protein levels are essential for the therapeutic efficacy of intravenous neural stem cells (NSCs) treatment in this animal model
Summary
Prenatal alcohol exposure is invariably detrimental to the developing central nervous system and can cause behavioral/ cognitive and mental/social problems, defined as fetal alcohol spectrum disorders (FASDs).[1,2] Abnormalities in cortical and limbic system development have been linked to FASD, but the underlying cellular pathogenesis in the brain remains elusive. What type of GABAergic cell development was influenced by prenatal ethanol exposure is unknown; the behavioral abnormalities observed in children affected with FASD include cognitive, executive and social/emotional dysfunctions, which are indicative of disruption in corticolimbic (including PV-containing) interneurons
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