Children with Fetal Alcohol Spectrum Disorder exhibit long lasting behavioral impairments, such as learning disabilities, problems in executive functioning and memory deficits. Currently, there are no rationally designed, clinically available pharmacological tools to circumvent prenatal alcohol-induced cognitive deficits. Recently, using a rat model of voluntary drinking during pregnancy, Savage and collaborators (2010) showed that the inverse agonist of histamine H3 receptors reverses fetal ethanol-induced deficits in learning and memory, without further increasing cognition in control rats. These differential effects and the notion that H3 receptors reside in presynaptic nerve terminals to inhibit neurotransmitter release, led to the hypothesis that fetal alcohol exposure elevates histamine H3 receptor-mediated depression of glutamate release from perforant path nerve terminals in the dentate gyrus, and that this effect may contribute to the observed long-term potentiation (LTP) deficit in these animals. In the present study, this hypothesis was examined using a combination of electrophysiological and radiohistochemical approaches. Long-Evans rat dams voluntarily consumed between 2.40 and 2.82 g/kg/day of 5% sweetened ethanol solution throughout gestation. This level of consumption produced a mean peak serum ethanol concentration of 84 mg/dL. No differences in offspring birthweight or litter size were observed. Prenatal alcohol exposure did not significantly affect electrophysiological raw measures of granule cell responsiveness or baseline probability of glutamate release in the dentate gyrus, but significantly impaired coupling of population spikes-to-fEPSP slopes and LTP of perforant path-to-granule cell synapses. Prenatal alcohol-induced LTP deficit was reversed by systemic injection of the inverse agonist of H3 receptors ABT-239 in-vivo, without further improvement in control rats. Conversely, agonism of these receptors by systemic injection of methimepip mimicked the LTP deficit in control offspring both in-vivo and in-vitro, without further decreasing LTP in prenatal alcohol exposed rats. Measurement of methimepip-stimulated binding of [35S]-GTPyS in the dentate gyrus in prenatal alcohol exposed rats suggested an increased H3 receptor-effector coupling in these animals. This increased receptor-effector coupling resulted in heightened agonist inhibition of glutamate release in-vitro, but not in-vivo. No differences were found in the density of histamine H3 receptors in the dentate gyrus. Taken together, these results suggest that heightened H3 receptor-mediated modulation of glutamate release in the dentate gyrus of fetal-ethanol exposed rats is a possible contributing mechanism for LTP deficit observed in these animals. It is expected that these experiments will provide insights into the mechanisms by which prenatal ethanol exposure affects hippocampal-dependent learning and memory. A better understanding of this phenomenon may provide targets for therapeutic intervention in children with alcohol-related neurodevelopmental disorders.
Fetal Alcohol Spectrum Disorder, Histamine, Histamine H3 Receptors, Dentate Gyrus, Glutamate, Synaptic Plasticity, Rats
National Institutes of Health; National Institute of Alcohol Abuse and Alcoholism.
Level of Degree
Biomedical Sciences Graduate Program
First Committee Member (Chair)
C. Fernando, Valenzuela
Second Committee Member
Third Committee Member
Varaschin, Rafael. "Prenatal alcohol exposure alters histamine H3 receptor modulation of glutamate release and long-term potentiation in the rat dentate gyrus." (2012). https://digitalrepository.unm.edu/biom_etds/67