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Developmental biology - Brain Disorders|
Imbalance between neurons disrupts development
To explore the impact of immune activation on the developing brain, researchers induced either maternal or postnatal immune activation, or gave both treatments to groups of pregnant mice and their offspring. Pregnant mothers were treated with polycytidylic acid, a chemical that simulates the effects of a viral infection, at a point in time that approximated the third trimester of pregnancy in humans. The offspring were treated with a lipopolysaccharide (LPS), a chemical that simulates a bacterial infection and causes a temporary (1-3 day) activation of the immune system. LPS was given at a point in time that approximates the stage of brain development in humans right at the time of birth, thus mimicking the development of a bacterial infection during delivery.
"Mounting evidence suggests that immune activation, such as prenatal viral infections and postnatal bacterial infections, can impact later life brain development in humans. While previous studies at McLean and elsewhere have focused on the behavioral symptoms produced by such immune activation, this study goes deeper, going to the cellular level to show how the brain's neural circuits are affected."
"Previous studies have helped demonstrate the types of things that can happen behaviorally as a result of immune system activation," added Bill Carlezon PhD, Chief of the Division of Basic Neuroscience at McLean Hospital, and co-senior author of the paper. "This research, however, is distinguishable in that it is an important step in telling us the biological basis of how these symptoms develop."
To explore the impact of immune activation on a developing brain, researchers induced an immune response in pregnant mother mice with polycytidylic acid, a chemical that simulates a viral infection. The timing approximated the third trimester of pregnancy in humans. Pups were treated with a lipopolysaccharide (LPS), a chemical that simulates a bacterial infection and causes a temporary (1-3 day) activation of the pups'immune system. LPS was given at a point in time approximating in humans the time of birth — and the corresponding stage of brain development. LPS mimicks development of a bacterial infection during delivery.
Long after the treatments were given, at a time in mice approximating young adulthood in humans, investigators examined the impact of the simulated infections on the brain, comparing results to those of mice having received non-LPS injections. Focusing on the neural pathway from the brain's prefrontal cortex to the amygdala, researchers combined optogenetics — a technique that uses light to control the activity of neurons in living tissue — with behavioral testing, a method that allows researchers to study functional connections between different regions of the brain.
Behaviorally, researchers found a strong connection between immune activation and symptoms of enhanced anxiety-like behavior that decreased social interactions. Correspondingly, they also found that neural circuits in the brain which contribute significantly to the control of anxiety and social interactions were significantly affected in immune-activated mice.
While the group receiving combined maternal and postnatal treatment showed the largest behavioral effects, electrophysiology easily distinguished the path of effects in each of the four groups. According to researchers, the ability to definitively detect and distinguish electrophysiological changes suggests the study provided a strong link between immune activation and brain disorder.
Bolshakov: "These results are novel. This sensitive and comprehensive testing has revealed how prenatal and early postnatal immune activation may regulate core behavior signs associated with ASD and certain developmental disorders — via changes to signals flowing between different components of behavior driven neural circuits. These findings may have significant value, providing important clues to mechanisms behind these disorders — and potential treatment."
Inflammatory processes may be involved in the pathophysiology of neuropsychiatric illnesses including Autism Spectrum Disorder (ASD). Evidence from studies in rodents indicates that immune activation during early development can produce core features of ASD (social interaction deficits, dysregulation of communication, increases in stereotyped behaviors and anxiety), although the neural mechanisms of these effects are not thoroughly understood. We treated timed-pregnant mice with polyinosinic:polycytidylic acid (Poly I:C), which simulates a viral infection, or vehicle on gestational day 12.5 to produce maternal immune activation (MIA). Male offspring received either vehicle or lipopolysaccharide (LPS), which simulates a bacterial infection, on postnatal day 9 to produce postnatal immune activation (PIA). We then used optogenetics to address the possibility that early developmental immune activation causes persistent alterations in the flow of signals within the medial prefrontal cortex (mPFC) to basolateral amygdala (BLA) pathway, a circuit implicated in ASD. We found that our MIA regimen produced increases in synaptic strength in glutamatergic projections from the mPFC to the BLA. In contrast, our PIA regimen produced decreases in feed-forward GABAergic inhibitory postsynaptic responses resulting from activation of local circuit interneurons in the BLA by mPFC-originating fibers. Both effects were seen together when the regimens were combined. Changes in the balance between excitation and inhibition were differentially translated into the modified spike output of BLA neurons. Our findings raise the possibility that prenatal and postnatal immune activation may affect different cellular targets within brain circuits that regulate some of the core behavioral signs of conditions such as ASD.
Immune system activation during prenatal and early postnatal development may contribute to the development of Autism Spectrum Disorder (ASD). Combining optogenetic approaches and behavioral assays that reflect core features of ASD (anxiety, decreased social interactions), we uncovered mechanisms by which the ASD-associated behavioral impairments induced by immune activation could be mediated at the level of interactions within brain circuits implicated in control of emotion and motivation (mPFC and BLA, specifically). In this article, we present evidence that prenatal and postnatal immune activation can have different cellular targets in the brain, providing support to the notion that the etiology of ASD may be linked to the excitation/inhibition imbalance in the brain affecting the signal flow within relevant behavior-driving neural microcircuits.
Authors: Yan Li, Galen Missig, Beate C. Finger, Samantha M. Landino, Abigail J. Alexander, Emery Mokler, James Robbins, Yunona Manasian, Woori Kim, Kwang-Soo Kim, Christopher J. McDougle, William A. Carlezon and Vadim Y. Bolshakov.
The authors declare no competing financial interests.
McLean Hospital is the largest psychiatric affiliate of Harvard Medical School and a member of Partners HealthCare. In 2017, it was named the #1 hospital for psychiatric care in the United States by U.S. News & World Report. For more information about McLean, visit mcleanhospital.org or follow the hospital on Facebook or Twitter.
We thank the Robert and Donna Landreth Family Foundation and the Nancy Lurie Marks Family Foundation for their generous support of this project.
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McClean Hospital new study backs up existing evidence that maternal immune activation can impact brain development in children. Researchers report immune activation during pregnancy or soon after birth can cause alterations to brain networks associated with social behavior, resulting in autism-like symptoms in the offspring. Image: McLean Hospital.