The effects of prenatal alcohol exposure on GABAergic interneuron migration in neurodevelopment
Introduction: Exposure to ethanol during early fetal development alters the development of the cortex as well as subcortical connections in the brain – these changes come under the umbrella of fetal alcohol spectrum disorders (FASD)1. Most notably, prenatal alcohol exposure (PAE) interferes with the tangential migration of GABAergic interneurons throughout the cortex at a time when they provide excitatory input to the developing brain1, 2. The mechanisms by which PAE causes birth defects and cognitive deficits are multifactorial and, at this time, poorly understood3. One of the major targets of ethanol in PAE is GABAA receptors – ethanol exposure depolarizes the reversal potential of GABAergic neurons in early development by dissolving the chloride gradient across the neuronal membrane and causes an imbalance between their excitatory and inhibitory effects4. The effects of maternal alcohol consumption are most pronounced in the medial prefrontal cortex (mPFC), which is likely responsible for many behavioral and social impairments seen in children with FASD2. Methods: To assess whether the excitation/inhibition imbalance of GABAergic neurons was attributable to impairment of chloride transport, KCCL2 chloride transporter activity was measured using patch-clamp electrophysiology in mice with PAE4. To assess the effects of PAE on the migration of GABAergic interneurons, pregnant mice were given ethanol in acute and chronic drinking patterns, and the offspring were either subjected to immunohistochemistry studies or grew to adulthood to assess behavioral alterations using open-field testing6. Results: KCCL2 was inactivated in the GABAergic interneurons of mice with a history of PAE when compared with control mice, and application of the drug CLP257 effectively reactivated this transporter4, 5. Immunohistochemistry studies of adult mice with a history of PAE revealed decreased GABAergic tone in layer V cortical pyramidal cells corresponding with inhibition of the mPFC6. Adult mice with histories of PAE have demonstrated hyperactivity with impairment in spatial learning and memory tasks, which reinforces the probability that behavioral abnormalities secondary to PAE persist through adulthood6. Conclusions: The mechanisms by which PAE affects the FASD phenotype are multifactorial, but two important pathways to consider are the excitatory/inhibitory imbalance of GABAergic interneurons4 and the impaired migration of these interneurons to important areas such as the medial prefrontal cortex6. Further research can elucidate how binge-drinking vs. chronic alcohol consumption affects the FASD phenotype and improve prenatal counseling to prevent early effects of PAE.
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