GABA Receptor Density Alterations Revealed in a Mouse Model of Early Moderate Prenatal Ethanol Exposure Using [F]AH114726

Introduction: Prenatal ethanol exposure (PEE) has been shown to alter the level and function of receptors in the brain, one of which is GABA receptors (GABAR), the major inhibitory ligand gated ion channels that mediate neuronal inhibition. High dose PEE in animals resulted in the upregulation of GABAR, but the effects of low and moderate dose PEE at early gestation have not been investigated. This study aimed at examining GABAR density in the adult mouse brain following PEE during a period equivalent to the first 3 to 4 weeks in human gestation. It was hypothesized that early moderate PEE would cause alterations in brain GABAR levels in the adult offspring.

Methods: C57BL/6J mice were given 10% v/v ethanol during the first 8 gestational days. Male offspring were studied using in-vivo Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI), biodistribution, in-vitro autoradiography using [F]AH114726, a novel flumazenil analogue with a high affinity for the benzodiazepine-binding site, and validated using immunohistochemistry.

Results: In vivo PET and biodistribution did not detect alteration in brain tracer uptake. In vitro radiotracer studies detected significantly reduced GABAR in the olfactory bulbs. Immunohistochemistry detected reduced GABAR in the cerebral cortex, cerebellum and hippocampus, while Nissl staining showed that cell density was significantly higher in the striatum following PEE.

Conclusion: Early moderate PEE may induce long-term alterations in the GABAR system that persisted into adulthood.