Fetal alcohol spectrum disorder (FASD) is a prevalent condition (2-5% in the U.S.) characterized by learning and memory alterations. Studies have shown that disruptions in the function of the hippocampus play a role in the pathophysiology of FASD. Our long-term goal is to identify the molecular and cellular mechanisms responsible for the effects of ethanol on the developing hippocampus. During the extension period of this Merit award, we propose to characterize ethanol?s effect on GABAergic hippocampal interneurons and to determine if the presence of a BDNF polymorphism increases vulnerability of the developing hippocampus to ethanol-induced damage.
Aim #1 will test the the hypothesis that developmental ethanol exposure persistently damages interneurons in the dentate gyrus. The flow of information into the hippocampal formation is gated by a diverse group of GABAergic interneurons whose migration and integration into the network take place during the rodent equivalent to the 2nd and 3rd trimesters of human pregnancy. We found that ethanol exposure of mice during the equivalent to these trimesters dramatically reduces the number of dentate gyrus interneurons. We will explore the mechanism responsible for this effect and characterize the morphology and function of surviving interneurons using electrophysiological and optogenetic techniques. We will assess whether ethanol exposure alters spatial memory and attempt to correct these behavioral deficits by stimulating interneurons using optogenetics or DREADDs.
Aim 2 will test the hypothesis that a BDNF polymorphism (Met68BDNF), that disrupts intracellular trafficking of immature BDNF and reduces activity-dependent release of this factor, increases the susceptibility of developing hippocampal neurons to ethanol-induced damage. We will assess the impact of developmental ethanol exposure on the morphology and function of hippocampal neurons in wild-type and Met68BDNF mice. We will investigate whether hippocampal-dependent behaviors are more severely affected by developmental ethanol exposure in Met68BDNF mice. These studies will lay the foundation for future translational studies on whether this polymorphism modulates the severity of FASD in humans.

Public Health Relevance

Prenatal exposure to ethanol is a leading cause of intellectual disabilities, including learning and memory deficits. We will investigate whether these deficits are a consequence of damage to a specialized group of brain cells that play a critical role in learning and memory. We will also determine if a variation in the gene for a neuronal survival-promoting factor increases susceptibility to these ethanol-induced cognitive deficits.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Cui, Changhai
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University of New Mexico Health Sciences Center
Schools of Medicine
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Bird, C W; Baculis, B C; Mayfield, J J et al. (2018) The brain-derived neurotrophic factor VAL68MET polymorphism modulates how developmental ethanol exposure impacts the hippocampus. Genes Brain Behav :e12484
Bird, Clark W; Taylor, Devin H; Pinkowski, Natalie J et al. (2018) Long-term Reductions in the Population of GABAergic Interneurons in the Mouse Hippocampus following Developmental Ethanol Exposure. Neuroscience 383:60-73
Kajimoto, Kenta; Valenzuela, C Fernando; Allan, Andrea M et al. (2016) Prenatal alcohol exposure alters synaptic activity of adult hippocampal dentate granule cells under conditions of enriched environment. Hippocampus 26:1078-87
Morton, Russell A; Valenzuela, C Fernando (2016) Further characterization of the effect of ethanol on voltage-gated Ca(2+) channel function in developing CA3 hippocampal pyramidal neurons. Brain Res 1633:19-26
Welch, J H; Mayfield, J J; Leibowitz, A L et al. (2016) Third trimester-equivalent ethanol exposure causes micro-hemorrhages in the rat brain. Neuroscience 324:107-18
Morton, Russell A; Valenzuela, C Fernando (2016) Third Trimester Equivalent Alcohol Exposure Reduces Modulation of Glutamatergic Synaptic Transmission by 5-HT1A Receptors in the Rat Hippocampal CA3 Region. Front Neurosci 10:266
Baculis, Brian Charles; Valenzuela, Carlos Fernando (2015) Ethanol exposure during the third trimester equivalent does not affect GABAA or AMPA receptor-mediated spontaneous synaptic transmission in rat CA3 pyramidal neurons. J Negat Results Biomed 14:19
Baculis, Brian C; Diaz, Marvin R; Valenzuela, C Fernando (2015) Third trimester-equivalent ethanol exposure increases anxiety-like behavior and glutamatergic transmission in the basolateral amygdala. Pharmacol Biochem Behav 137:78-85
Morton, Russell A; Yanagawa, Yuchio; Valenzuela, C Fernando (2015) Electrophysiological Assessment of Serotonin and GABA Neuron Function in the Dorsal Raphe during the Third Trimester Equivalent Developmental Period in Mice. eNeuro 2:
Topper, Lauren A; Baculis, Brian C; Valenzuela, C Fernando (2015) Exposure of neonatal rats to alcohol has differential effects on neuroinflammation and neuronal survival in the cerebellum and hippocampus. J Neuroinflammation 12:160

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