Fetal alcohol spectrum disorders (FASD) and associated neurologic sequelae occur in 1-5 of 100 births in the U.S. There is no cure. The overarching goal of our research is to understand the molecular mechanisms that lead to neurologic deficits of FASD and, with this knowledge, identify pharmaceutical interventions. Studies in FASD animal models show that alcohol (ethanol) causes loss of hippocampal neurons, impaired synaptic plasticity in hippocampal neurons, and deficits in learning and memory. Our studies in the neonatal mouse model of FASD demonstrate that ethanol induces neuroinflammation in the developing hippocampus including microglial activation and production of pro-inflammatory cytokines and chemokines. Ethanol induction of neuroinflammation in the hippocampus is particularly important to FASD since recent studies demonstrate neuroinflammation during brain development can produce life-long cognitive disorders. The studies proposed here will investigate whether ethanol-induced inflammation is linked to the long-term cognitive deficits in FASD. Further, our studies further demonstrate that treatment with anti-inflammatory peroxisome proliferator activated receptor-? (PPAR-?) agonists protect against ethanol-induced microglial activation and expression of inflammatory molecules in the developing hippocampus. Collectively, this evidence suggests neuroinflammation in the developing hippocampus may contribute to long-term cognitive deficits in FASD. However, critical gaps in knowledge must be addressed before this information can be used toward the treatment of FASD. The proposed studies will test the hypothesis that ethanol induction of neuroinflammation contributes to long-term learning and memory deficits associated with FASD, and anti-inflammatory agents, including PPAR-? agonists, can block these ethanol effects. We will test this hypothesis using our well- established neonatal mouse model of FASD, which represents human third-trimester fetal alcohol exposure.
Aim 1 will determine the mechanisms of ethanol-induced neuroinflammation in the developing hippocampus. The role of (A) TLR4 and downstream signaling, (B) NLRP3 inflammasome activation, and (C) CX3CL1? CX3CR1 signaling in ethanol-induced neuroinflammation and neuron loss will be investigated using transgenic mice with genetic knockout of key molecules in these signaling pathways.
Aim 2 will determine if ethanol- induced neuroinflammation contributes to long-term impairment of hippocampal synaptic plasticity and long- term learning and memory deficits in FASD, and if suppression of neuroinflammation prevents these deficits. (A) Establish whether TLR4 and downstream signaling, NLRP3 inflammasome activation, and/or CX3CL1? CX3CR1 signaling play a critical role in long-term synaptic plasticity and learning and memory deficits using transgenic mice with genetic knockout of key molecules in these signaling pathways. (B) Evaluate whether anti-inflammatory PPAR-? agonists protect against ethanol impairment of synaptic plasticity and cognitive deficits.
Although fetal alcohol spectrum disorders (FASD) occur in 1-5 of 100 births in the U.S. with cognitive deficits that persist throughout life, there is no treatment. The goal of the proposed research is to understand the molecular mechanisms that lead to cognitive deficits in FASD and, with this knowledge, identify pharmaceutical interventions. Because our research in clinically translational FASD mouse models has recently revealed that alcohol causes neuroinflammation in the developing hippocampus, the proposed studies will use innovative genetic and pharmacological approaches to: (1) probe the hypothesis that ethanol induction of neuroinflammation in the developing hippocampus contributes to cognitive deficits in FASD, and (2) provide proof-of-principle that anti-inflammatory agents such as PPAR-? agonists can suppress ethanol-induced neuroinflammation to prevent or treat cognitive deficits in FASD.
