Nature Prenatal immunostress impairs microglial activity and neural circuits

Written by | A fish

Microglia are major immune cells in the brain that influence neural circuit connections and neuronal function [1].

As early as embryonic development, microglia penetrate into the neuroepithelium and persist in the brain throughout adulthood [2,3].

Some maternal environmental factors affect prenatal brain development [4,5], but it remains unclear
whether the prenatal environment affects the developmental trajectory of infiltrating microglia and thus brain development and function.

Recently, Akira Sawa's research team from Johns Hopkins University School of Medicine published an article in Nature entitled Prenatal immune stress blunts microglia reactivity, impairing neurocircuitry, and found that mouse maternal immune activation ( MIA) leads to a long-term decrease in immune activity during the development of offspring microglia, which is related to the degree of chromatin openness and transcription factor occupation, and the prenatal replacement of microglia in MIA offspring with physiologically infiltrated naïve microglia can alleviate the weakening of the immune response and rescue its impact
on neuronal function.

To investigate whether maternal immune activation (MIA) affects microglial function, the researchers administered polyinosinate-polycytidylate (PIC) immunotreatment to pregnant mice during the first wave of microglia infiltrating the neuroepithelium, that is, at 9.
5 days (E9.
5) of the embryo.

After the offspring mice became adults, lipopolysaccharide (LPS) activated inflammatory response or normal saline (SAL) treatment, microglia were isolated, gene expression profiles were detected, and most of the differentially expressed genes (DEGs) were downregulated, including many immune response pathways
。 Therefore, microglia treated with MIA lead to a significant decrease
in immune activity in adulthood.

MIA causes a weakened microglial immune response

Next, they extracted microglia from the striatum and cortex of adult offspring mice after MIA-treatment, cultured them in vitro, stimulated with LPS, and then examined the levels of the secreted cytokines IL-6 and TNFα, and found that the secreted cytokines decreased
levels.
Even in microglia extracted from the striatum of mice E18 days after MIA treatment, they detected a similar weakening of the immune response, so prenatal immune activation leads to a long-term
decline in the immune response of microglia during development.

In addition, they found that differentially expressed genes for MIA were enriched in genes for risk of schizophrenia, a neurodevelopmental disorder in which symptoms usually appear
after puberty.
Although the level of cytokines in the cerebrospinal fluid of schizophrenia patients is usually increased, brain imaging shows that cellular immune activation is not significantly increased, or even decreased [6-8], which is also consistent
with their findings.
Thus, dysfunctional microglia during development may be involved in the development
of schizophrenia.

So how does MIA lead to a decreased immune response in adulthood? They hypothesized that epigenetic changes may inhibit transcriptional regulation
of immune activation.
They treated the microglia of adult MIA with LPS and then performed chromatin open sequencing ATAC-seq and found that 97% of the heterogeneous accessible areas were more open
.

How does open chromatin structure lead to weakening of immunotranscription procedures? To address this problem, they used transcription factor footprint analysis to quantitatively assess transcription factors occupying open chromatin regions and found that 76 percent of 83 differentially occupied transcription factors showed less occupancy, including GATA4, SMAD3, and STAT1
, which regulate the immune response.
Thus, after LPS treatment, microglial chromatin in adult MIAs is more open, but fewer transcription factors occupy these open regions, which leads to weakened
transcriptional activation of immune response genes.

Is it possible to alleviate the deactivation of the microglial immune response caused by MIA by removing the microglia affected by MIA so that naïve microglia can re-infiltrate the developing brain? To achieve prenatal microglial replacement, they treated female mice pregnant between E9.
5 and E12.
5 with a CSF1R antagonist (PLX5622) to remove myeloid cells (microglia are derived from myeloid cells), performed gene expression analysis in adulthood, and found that replacing MIA microglia alleviated immune passivation
.

Next, to study the cellular non-autonomous effects of MIA microglia on peripheral neurons and glia, they examined the response of astrocytes and non-microglia/non-astrocytes to LPS and found that these cells produced increased levels of IL-6, indicating an enhanced immune response, while prenatal microglial replacement could inhibit the immune enhancement
of astrocytes.

To examine the cellular involuntary effects of MIA microglia on brain development and neuronal function, they examined the electrophysiology of medium-sized multispiny neurons (MSNs) in the ventral striatum of adult MIA offspring mice and found spontaneous excitatory postsynaptic currents of MSNs of dopamine type 2 receptors (D2R).
Decreased frequency of (sEPSC) and microexcitatory postsynaptic current (mEPSC) indicates a reduced
probability of presynaptic vesicle release.
Also, prenatal microglial replacement can save the mEPSC frequency of D2R MSNs back to normal levels, so post-MIA microglia can cause abnormal
connections in the ventral striatal neural circuit.

Overall, this study reveals how microglia infiltrated during early brain development are affected by the prenatal environment, prenatal immune stimulation reduces microglial activity, these microglial dysfunctions are not obvious under normal conditions, but when it is necessary to respond to external or internal immune stimuli, the response is weakened, and the reduced activity of microglia causes an enhanced astrocytes inflammatory response in adult offspring of MIA, therefore, Prenatal prevention or treatment may be a new idea
for the treatment of related neurological disorders.