Fetal alcohol spectrum disorder (FASD) is a prevalent disorder characterized by learning and memory deficits that are likely a consequence of alterations in synapse formation, refinement and/or maintenance. During the previous funding period, we showed that 3rd trimester-equivalent ethanol (EtOH) exposure alters activity- dependent plasticity mechanisms that are essential for synapse maturation. In the most recent of these studies, we demonstrated that EtOH potently inhibits a form of synaptic plasticity that depends on local, retrograde release of BDNF from CA3 pyramidal neuron dendrites that is triggered by activation of L-type voltage-gated Ca2+ channels (L-VGCCs). Our hypothesis is that chronic EtOH exposure during the 3rd trimester equivalent persistently inhibits L-VGCCs, leading to a decrease in synaptic plasticity dependent on local retrograde BDNF release and ultimately causing delayed maturation of CA3 pyramidal neuron synapses.
Aim #1 is to test the hypothesis that chronic EtOH causes persistent L-VGCC inhibition by inducing channel degradation via depletion of internal Ca2+ stores and STIM1 binding to 11 subunits. Using slice electrophysiological and Ca2+ imaging techniques, we will assess whether EtOH exposure causes persistent functional inhibition of L-VGCCs. We will also determine whether EtOH exposure decreases plasma membrane expression of L-VGCC subunits using a surface biotinylation assay. Using Ca2+ imaging, co- immunoprecipitation and immunhistochemical techniques, we will investigate if these effects are a consequence of depletion of internal Ca2+ stores and STIM1 binding to CaV11.2/1.3.
Aim #2 is to test the hypothesis that chronic EtOH inhibits L-VGCC/BDNF-dependent plasticity at mossy fiber-CA3 pyramidal neuron synapses. At these synapses, L-VGCC-dependent retrograde release of BDNF induces spike timing- dependent long-term potentiation and we will investigate if this form of synaptic plasticity is inhibited by EtOH exposure using slice electrophysiological techniques.
Aim #3 is to test the hypothesis that EtOH-induced inhibition of L-VGCC-dependent retrograde release of BDNF impairs the maturation of interneuron- and MF- CA3 pyramidal neuron synapses using slice electrophysiological and immunohistochemical techniques. We will also use a novel in vivo neonatal electroporation/shRNA experimental paradigm to determine if selective downregulation of L-VGCC or BDNF expression in CA3 pyramidal neurons mimics the effect of chronic EtOH on development of these synapses. Collectively, the proposed studies will define L-VGCC/BDNF dysfunction as a key element in the pathophysiology of FASD, forming the basis for the rational development of therapeutic interventions against this prevalent disorder. Results will also provide strong evidence supporting the recommendation that even light drinking during the 3rd trimester could adversely affect fetal brain development.
The hippocampus is a portion of the brain that is involved in learning and memory. Fetal alcohol exposure profoundly affects normal hippocampal functioning and our understanding of the mechanisms responsible for these effects is very limited. The goal of this project is to characterize the effect of alcohol on communication between developing hippocampal neurons, hopefully suggesting novel therapeutic interventions against fetal alcohol syndrome.
|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|
|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|
|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|
|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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