Role of Microglia in Prenatal ethanol exposure-induced Impairment of Endocannabinoid Signaling

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Prenatal ethanol exposure (PE) leads to fetal alcohol spectrum disorders (FASD), which consist of many cognitive/behavioral deficits including learning disabilities, attention and executive function deficits, increased addiction risk, and mood disorders. FASD is the most preventable neurodevelopmental disorder, yet the prevalence is still high which is at least 2-5% in the US and the world. Therefore, developing effective interventions is an important goal for FASD research. Persistent synaptic dysfunctions including immature synapses are critical cellular mechanisms mediating cognitive/behavioral deficits in FASD. Currently, the underlying mechanisms for these effects are not clear. We have shown PE leads to microglial activation and aberrant endocannabinoid (eCB) signaling during adulthood. Both microglia and eCB signaling play a critical role in the maturation, maintenance, and regulation of synaptic functions in the brain. Furthermore, increased eCB release from activated microglia has been reported to counter neuroinflammation. We have also observed that reducing microglial activation is associated with normalized eCB signaling, synaptic functions, and behaviors in PE animals. These observations lead to our central hypothesis that PE-induced persistent microglial activation leads to aberrant tonic eCB signaling, which contributes to long-lasting impairments in synaptic maturation/dysfunctions and behavioral deficits. This hypothesis will be verified using the ventral tegmental area dopaminergic (VTA DA) neurons as a model system because these neurons represent an excellent approach for studying eCB signaling and synaptic functions. Furthermore, persistent microglial activation, aberrant tonic eCB signaling, and impaired synaptic maturation/dysfunctions have been observed in the VTA. The PE-induced synaptic dysfunctions of VTA DA neurons are also associated with a clearly defined behavioral deficit - increased addiction risk. There are three Specific Aims utilizing multidisciplinary approaches to systematically verify the central hypothesis. Aim 1 will thoroughly characterize the dose and sex effects of PE-induced impairments in tonic eCB signaling, synaptic maturation/homeostasis, and microglial activation. Aim 2 will test the hypothesis that PE- induced aberrant tonic eCB signaling is caused by increased eCB synthesis/release from activated microglia. Aim 3 will test the hypothesis that reducing microglial activation in PE animals can restore synaptic dysfunctions and behavioral deficits. The results of the proposed studies will lead to important understanding in the cellular mechanisms mediating the persistent cellular and cognitive/behavioral deficits of PE. The results also fill a knowledge gap regarding how PE impacts the neuron/microglia interaction, a new exciting area of research. Lastly, the approach employs various methods aiming at reducing microglial activation to rescue cellular and behavioral deficits induced by PE. Therefore, the results can be readily translated to intervention strategies for FASD.