Impaired Pavlovian Conditioning and Altered Hippocampal N-methyl-D-aspartate Receptor Subunit Composition in a Rat Model of Fetal Alcohol Spectrum Disorder
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Date
2014-12
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The Ohio State University
Abstract
Fetal Alcohol Spectrum Disorders (FASD), resulting from gestational alcohol consumption, is marked by physical and mental abnormalities, including persistent impairments in learning and memory. In this study, rat pups were intragastrically intubated with alcohol (5E rats; 5g/kg/day) or sham intubated across postnatal days 4-9. Adult 5E rats were significantly impaired in trace fear conditioning (TFC), a Pavlovian conditioning paradigm in which the conditioned stimulus (tone) and the unconditioned stimulus (foot shock) are separated by a stimulus-free interval of time. TFC requires hippocampal and prefrontal cortex N-methyl-D-aspartate receptor (NMDAR) activation. NMDARs contain four subunits: two mandatory NR1 subunits and two regulatory NR2 subunits. When activated, NR2B-containing NMDARs gate more calcium than NR2A-containing NMDARs. Calcium acts as a second messenger in a molecular signaling cascade that contributes to the induction and maintenance of long-term potentiation (LTP), a learning-mediated enhancement of neural signaling, on which successful TFC is reliant. Thus, NR2B subunits are proposed to enhance learning-dependent LTP more so than NR2A, and ethanol-induced alterations to NMDAR subunit composition could disrupt LTP maintenance and long-term memory storage. In support, whole cell lysate Western blotting revealed an elevated NR2A/NR2B ratio in dorsal hippocampus, but not in ventral hippocampus or medial prefrontal cortex, of adult 5E rats. Utilizing subcellular fractionation, Western blotting showed a significant reduction in synaptic and extrasynaptic NR2B subunits in dorsal hippocampus of 5E rats, which is proposed to impede the synaptic plasticity required for successful TFC. Results are expected to provide new and valuable knowledge regarding the etiology of FASD, and may lead to the use of novel pharmacological therapies targeting NMDARs to ameliorate cognitive deficits in FASD individuals.
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Undergraduate Research Scholarship