What the Spectrum of Microglial Functions Can Teach us About Fetal Alcohol Spectrum Disorder

Abstract

Alcohol exposure during gestation can lead to severe defects in brain development and lifelong physical, behavioral and learning deficits that are classified under the umbrella term fetal alcohol spectrum disorder (FASD). Sadly, FASD is diagnosed at an alarmingly high rate, affecting 2%-5% of live births in the United States, making it the most common non-heritable cause of mental disability. Currently, no standard therapies exist that are effective at battling FASD symptoms, highlighting a pressing need to better understand the underlying mechanisms by which alcohol affects the developing brain. While it is clear that sensory and cognitive deficits are driven by inappropriate development and remodeling of the neural circuits that mediate these processes, alcohol's actions acutely and long-term on the brain milieu are diverse and complex. Microglia, the brain's immune cells, have been thought to be a target for alcohol during development because of their exquisite ability to rapidly detect and respond to perturbations affecting the brain. Additionally, our view of these immune cells is rapidly changing, and recent studies have revealed a myriad of microglial physiological functions critical for normal brain development and long-term function. A clear and complete understanding of how microglial roles on this end of the spectrum may be altered in FASD is currently lacking. Such information could provide important insights toward novel therapeutic targets for FASD treatment. Here we review the literature that links microglia to neural circuit remodeling and provide a discussion of the current understanding of how developmental alcohol exposure affects microglial behavior in the context of developing brain circuits.

Developmental alcohol exposure impairs synaptic plasticity without overtly altering microglial function in mouse visual cortex

“…We chose to focus on microglial functions after developmental EtOH exposure because of the many diverse and complex roles that these cells play, from being ‘immune sentinels’ that can detect and resolve insults in the diseased brain to also being ‘gardeners’ that can selectively prune synaptic connections and support neuronal health under physiological conditions (as reviewed by (Hughes, 2012; Rohan Walker and Yirmiya, 2016; Tremblay et al, 2011; Wong et al, 2017). Currently, a body of work suggests that microglial immune functions may be triggered by high binge levels of EtOH exposure.…”

Microglia and astrocytes show limited, acute alterations in morphology and protein expression following a single developmental alcohol exposure

“…Given the roles of microglia in synaptic circuit formation and rearrangement (Ikegami et al, 2019), disruption of these functions could directly cause neuropathology found in FASD. Previous research in the field has already demonstrated both direct and indirect negative effects of developmental alcohol on microglia (reviewed in (Wong et al, 2017)). Our findings suggest that microglia may be sensitive to as little as one dose of EtOH in early development, which supports other studies showing similarly fast microglial responses to EtOH (Ahlers et al, 2015).…”

Dynamics of microglia and dendritic spines in early adolescent cortex after developmental alcohol exposure

“…The effects of early exposure to ethanol exposure on microglia Neuroimmune changes have been reported after both adult and developmental EtOH exposure. Microglia are critical for neuronal development and are highly reactive to disturbances in the brain milieu making them likely targets for EtOH exposure (Wong et al, 2017). In fact, changes in microglia have been reported throughout the brain in animal models of developmental EtOH exposure, including exposure limited to the BGS (Kane &Drew, 2020).…”