Page 77 - AN-1-3

Advanced Neurology Microglia in autism spectrum disorder

for removing debris during CNS development and in immune activation (MIA) is believed to be a cause of
pathological conditions. Microglia-mediated immune ASD . Studies have demonstrated that infection during
[10]
inflammation was believed to affect the stability of the pregnancy, especially in the first trimester, is a risk factor
CNS . With the advances in genetic technologies and for the development of ASD in offspring . MIA models
[6]
[11]
single-cell analysis, the connection between microglia and were induced using polyriboinosinic polyribocytidylic
neurons has become more apparent. Besides being central acid (poly[I: C]), lipopolysaccharides (LPS), valproic acid
to the inherent immune response, microglia are involved treatment, simulated viral and bacterial infections, as well
in a variety of neuropsychiatric diseases; functional as other environmental factors to activate the maternal
[12]
abnormalities of microglia have been confirmed in anxiety, immune system and test possible autistic-like behavioral
depression, and other mental disorders. Therefore, the manifestations in offspring (Figure 1).
mechanism of action of microglia in mental illness is one Stimulation of certain physicochemical factors during
of the trending topics in current research. The modulation pregnancy also leads to a significantly increased risk of
of neuronal activity by microglia is evident in many brain ASD in offspring. It has been reported that exposure to
diseases . valproic acid during pregnancy increases the probability
[7]
[13]
The dysfunction of microglia may be one of the of ASD in offspring by 50% . Studies of the early
[8]
underlying mechanisms in ASD . Aberrant activity of pregnancy diets have shown that propionic acid salt
microglia, abnormal levels of associated inflammatory might accumulate in the gastrointestinal tract of pregnant
factors, and certain cellular pathways have been observed women who consume processed foods that are rich in
in autistic patients and animal models. Both genetic and propionate. Propionate can pass through the placental
environmental factors that affect microglia may be involved barrier, bind with G-protein receptors 41 (GPR41) on glial
in the etiology of ASD . The deletion or amplification of progenitor cells, and cause impaired neural differentiation.
[9]
certain genes may cause ASD, and changes in the peripheral Furthermore, the expression of downstream phosphatase
environment may affect microglia, further aggravating and tensin homolog deleted on chromosome 10 (PTEN) is
autism-like behaviors. inhibited, and protein kinase B (PKB) pathway is activated
to promote the proliferation and differentiation of glia.
In this review, we propose that microglia are related Subsequently, glial cells continue to produce inflammatory
to the development and progression of ASD. Several cytokines and release glial fibrillary acidic protein (GFAP)
widely accepted theories on the etiology of ASD and ASD after maturation, thus affecting the development of the
models are discussed. We focus on the mechanistic role of fetal nervous system.
microglia in ASD from the perspective of phagocytosis and
synaptic pruning, which affect neuronal activity, through 3. Role of microglia in ASD
the release of inflammatory factors and their influence Microglia, the innate immune cells of the CNS, have
on inflammatory pathways. We also summarize several high plasticity and can react rapidly during pathological
intervention approaches for ASD by modulating microglia processes. Microglia have been implicated to play a
and analyze the current challenges in treating ASD by crucial role in the development of ASD associated with
regulating microglia in hope that this review will make CNS inflammation . Recent advances have shown that
[14]
modest contributions to the early diagnosis and treatment microglia function far beyond the classical innate immune
of ASD. response and are involved in various processes, such as
2. Etiology of ASD and its pathogenesis neuronal excitation, synaptic pruning, and remodeling [15,16] .
A growing number of studies have demonstrated that the
The etiology of ASD is still unknown. Epidemiological biological role of microglia has a close association with
studies, screening for many possible risk factors, could ASD . As early as 2005, the significant activation of
[17]
not identify a direct contributor to the development of microglia and astrocytes in the brains of autistic patients has
ASD. Although the etiology of the disease is not fully been reported by Diana et al. . Since microglia activation
[18]
understood, genetic factors, manifested as deletion is the main cellular response to CNS dysfunction, it is
or abnormal insertion of specific genes, and gene- conceivable that abnormal glial cell is inextricably linked
environment interactions might lead to autistic-like to ASD.
behaviors. For example, genes such as CNTNAP2, NLGN3,
and SHANK3 have been shown to be associated with ASD. 3.1. Microglia mediate abnormal neuronal synapse
Cntnap2 knockout mice, Nlgn3 knock-in mice, and partial pruning/clearing
knockout of Shank3 gene are the common genotypes used Microglia are involved in the pruning and clearance
to construct ASD animal models. In addition, maternal of neuronal synapses. Rosa et al. have reported the
[19]

Volume 1 Issue 3 (2022) 2 https://doi.org/10.36922/an.v1i3.167