Abstract
Neurodevelopmental disorders, which emerge early in development, include a range
of neurological phenotypes and exhibit marked differences in prevalence between
sexes. A male predominance is particularly pronounced in autism spectrum
disorder (ASD). Although the precise cause of ASD is still unknown, certain
genetic variations and environmental influences have been implicated as risk
factors. Preclinical ASD models have been instrumental in shedding light on the
mechanisms behind the sexual dimorphism observed in this disorder. In this
review, we explore the potential processes contributing to sex bias by examining
both intrinsic differences in neuronal mechanisms and the influence of external
factors. We organize these mechanisms into six categories: 1) sexually dimorphic
phenotypes in mice with mutations in ASD-associated genes related to synaptic
dysfunction; 2) sex-specific microglial activity, which may disrupt neural
circuit development by excessively pruning synapses during critical periods; 3)
sex steroid hormones, such as testosterone and allopregnanolone, that
differentially influence brain structure and function; 4) escape from X
chromosome inactivation of the O-linked-N-acetylglucosamine transferase gene in
the placenta; 5) sexually dimorphic activation of the integrated stress response
pathway following maternal immune activation; and 6) immunological responses
that are differentially regulated by sex. Understanding these mechanisms is
essential for deciphering the underlying causes of ASD and may offer insights
into other disorders with notable sex disparities.
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Keywords: Autism spectrum disorder; Genetic variation; Pregnancy; Risk factors; Sex characteristics
Introduction
Background
Neurodevelopmental disorders (NDDs) are a heterogenous group of conditions that
manifest during the developmental period and are characterized by impairments in
various aspects of neurological functioning [
1]. As defined by the Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition, NDDs include autism spectrum disorder (ASD),
intellectual disability/developmental delay, attention-deficit/hyperactivity
disorder, motor and tic disorders, and specific language disorders. These
conditions can lead to a range of developmental deficits, from specific
challenges in learning or executive function management to more extensive
impairments in social skills or intellectual abilities [
2]. This review is primarily focused on ASD, a NDD marked by
deficits in social interaction and engagement in repetitive and stereotyped
behaviors [
2].
The prevalence, age of onset, pathophysiology, and symptomatology of many NDDs
vary substantially by sex. A pronounced male bias is evident in ASD, with a
male-to-female prevalence of approximately four to one [
3,
4]. The potential
underdiagnosis of females with ASD has raised concerns, suggesting the need for
distinct diagnostic criteria in their assessment [
5,
6]. Even apart from
variations in diagnostic practices, a sex bias persists in the prevalence of
ASD, with a male-to-female ratio ranging from at least 2:1 to 3:1. This
highlights the critical need to explore the biological basis of sexual
dimorphism, which may be key to understanding the processes underlying ASD
pathogenesis [
7].
Here, we explore the potential mechanisms contributing to the sex-biased
prevalence disparity in ASD using various preclinical models (
Table 1). While preclinical rodent models
of ASD cannot fully replicate the spectrum of human ASD phenotypes [
8], potentially due to differences in brain
structures and developmental trajectories [
9], they remain invaluable for gaining mechanistic insights into the
pathogenesis of ASD and for exploring potential therapeutic strategies [
10,
11].
Table 1.Potential contributing mechanisms underlying the sex-biased
prevalence of ASD as demonstrated in preclinical rodent models
|
Potential contributing
mechanisms |
Preclinical models showing sexually
dimorphic ASD-like phenotypes |
Suggested mechanism(s) |
References |
|
Synaptic dysfunction |
Shank3 KO |
Reduced levels of mGluR5 in male
mice |
[27] |
|
Chd8+/N2373K
|
Sexually dimorphic changes in neuronal
activity, synaptic transmission, and transcriptomic
profiles |
[40] |
|
Fmr1 KO |
Sexually dimorphic upregulation of ASD
risk genes
(male↑: Ctnnb1a and Grin1a, female↑:
Homer1a,
Ptgs2a,
Drd1a, Pik3cab, and Csnk1g1b) |
[44] |
|
Microglial
abnormalities |
Cntnap2 KO |
Activated morphology and phagocytosis
of synaptic structures in male microglia |
[58] |
|
DEP/MS |
Hyper-ramified phenotype in male
microglia |
[63] |
|
Hormones |
VPA-induced ASD mouse model |
Lower levels of TH expression in the
AVPV of male mice |
[70] |
|
Placenta-specific
Akr1c14 KO |
Male mouse-specific abnormalities in
cerebellar white matter |
[75] |
|
Escape from X chromosome
inactivation |
Prenatal stress model |
Placental OGT expression levels are
twice as high for female fetuses as for male fetuses; this
results in sexually distinct gene expression in trophoblasts
through epigenetic modulation by histone methylation |
[79,80] |
|
Integrated stress response
pathway |
MIA (Poly[I:C]) |
Hyperactivation of the ISR pathway in
male MIA offspring, resulting in reduced nascent protein
synthesis in the brain |
[85] |
|
Immune pathways |
Prenatal GBS infection |
Heightened levels of pro-inflammatory
cytokines and chemokines such as IL-1β and CINC-1/CXCL1
in male fetuses |
[98] |
|
MIA (LPS) |
Male MIA offspring exhibit heightened
cortical hypoxia, reduced mitosis of radial glial cells,
disrupted E/I balance within the brain, severe placental
necrosis, elevated inflammation, and reduced placental
growth |
[99] |
|
MIA (two-hit model) |
The anti-inflammatory cytokines IL-10
and TGF-β1 are decreased in male offspring but increased
in female mice |
[100] |
This review aims to elucidate the potential contributing mechanisms underlying
the sex-biased prevalence of ASD as demonstrated in preclinical rodent models.
These include synaptic dysfunction, microglial abnormalities, the influence of
sex hormones, escape from X chromosome inactivation, the integrated stress
response (ISR) pathway, and immune pathways.
Methods
Ethics statement
The present study is based on a review of the literature; consequently, neither
approval from an institutional review board nor the acquisition of informed
consent was necessary.
Study design
This study is a narrative review.
Literature search: information sources and search strategies
We searched the PubMed database for articles published from 1990 up to April
2024. Only articles published in English were included.
Results
This review encompasses a total of 104 articles. A list of articles pertaining to
each topic is available in the references.
Synaptic dysfunction
Previous studies have reported that those with ASD exhibit different brain
connectivity patterns compared to typically developing individuals [
12]. Patterns of widespread cortical
underconnectivity, local overconnectivity, or a combination of these suggest
that disrupted brain connectivity may represent a potential neural signature of
ASD [
13]. Brain connectivity is largely
determined by the characteristics of neurons and synapses, with synapses being
highly specialized, asymmetric cell-to-cell junctions that constitute the
fundamental units of brain communication [
14].
According to the Simons Foundation Autism Research Initiative (SFARI) gene
database, hundreds of genes have been identified as being associated with ASD
[
15–
18]. Among these, genes such as those of the SH3 and
multiple ankyrin repeat domains (
SHANK) family, fragile X
mental retardation 1 (
FMR1), and chromodomain helicase
DNA-binding protein 8 (
CHD8) are linked to common cellular
pathways that converge at synapses [
19–
21]. This
convergence suggests that synaptic dysfunction may contribute to the development
of ASD, potentially leading to functional and cognitive impairments [
14].
SHANK, also known as ProSAP, is a family of postsynaptic proteins found at
glutamatergic synapses and includes three major isoforms: SHANK1, SHANK2, and
SHANK3. These proteins act as master scaffolding proteins at excitatory synapses
[
22,
23]. They interact with over 30 synaptic proteins across multiple
domains and are critical for synaptic formation, glutamate receptor trafficking,
and neuronal signaling [
24]. Genetic
screenings have identified mutations, rare variants, or disruptions of the
SHANK3 gene in patients with ASD [
22]. Mice with a genetic disruption of
Shank3 display compulsive/repetitive behaviors and social
interaction deficits, which reflect clinical features of ASD [
25]. Studies using
Shank3
knockout (KO) mouse models have reported sexually dimorphic phenotypes [
26,
27]. Matas et al. found that male
Shank3 KO mice
with a mutation in the C-terminal regions (exons 21–22) [
28] exhibit more pronounced gait deficits
than their female siblings [
27]. Further
research into cerebellar glutamate levels and postsynaptic receptors showed that
metabotropic glutamate receptor 5 levels were reduced only in male
Shank3 KO mice, suggesting a potential cause for the varied
behavioral outcomes [
27].
CHD8, a chromatin remodeling factor, is essential for regulating the
transcription of a wide variety of genes [
29,
30], including
approximately 1,000 ASD risk genes identified in the SFARI gene database [
30]. Mice with homozygous deletions of
Chd8 die early in embryonic development [
31], while those with heterozygous
mutations or gene knockdown display a range of ASD-like phenotypes [
32–
36]. These include impaired social interaction, repetitive
behaviors, and cognitive impairments, resembling characteristics of individuals
with
CHD8 mutations [
20,
30,
37–
39]. Jung
et al. found that a heterozygous mutation in
Chd8, specifically
the substitution of asparagine with lysine at position 2373—the first
mutation identified as an ASD risk factor in human
CHD8—results in sexually dimorphic effects that range
from transcriptional to behavioral changes in mice [
40]. Male
Chd8+/N2373K mice
exhibited various abnormal behaviors at the pup, juvenile, and adult stages,
such as increased ultrasonic vocalizations when seeking their mother, heightened
attachment upon reunion with their mother, and increased self-grooming when
isolated. In contrast, their female counterparts did not exhibit these
behaviors. This behavioral disparity is thought to be associated with sexual
dimorphism in neuronal activity, synaptic transmission, and transcriptomic
profiles.
The
FMR1 gene encodes the fragile X mental retardation protein
(FMRP), which acts as a messenger RNA-binding translational suppressor. It also
modulates activity-dependent calcium signaling during critical developmental
periods [
41]. In mice, FMRP is most
abundantly expressed in the hippocampus and cerebral cortex, with peak levels
occurring between 2 to 4 weeks postnatally—a crucial time frame for
synaptic development and maturation [
42].
A deficiency in FMRP results in abnormal synaptic plasticity and structural
remodeling [
43]. Notably, male
Fmr1 KO mice exhibit more severe anxiety, deficiencies in
social preference, and repetitive behaviors than their female counterparts
[
44]. Differential gene expression
analysis of the hippocampus in wild-type (WT) versus
Fmr1 KO
mice revealed that in male
Fmr1 KO mice,
Ctnnb1 and
Grin1—genes considered
high-confidence risk factors for ASD—are highly upregulated. In contrast,
female
Fmr1 KO mice exhibited upregulation of genes such as
Homer1,
Ptgs2, and
Drd1,
which are strong ASD risk gene candidates, as well as
Pik3ca
and
Csnk1g1, which provide suggestive evidence of risk for ASD.
These findings suggest that the loss of FMRP leads to sexually dimorphic
phenotypes, potentially due to different patterns of gene expression regulation
resulting from the absence of FMR1.
The collective evidence from these reports suggests that synaptic dysfunction and
disrupted connectivity could be responsible for sex-specific functional and
cognitive impairments observed in ASD [
45].
The balance between excitation and inhibition (E/I) in neural circuits is
critical for maintaining brain homeostasis [
46]. Disruption of this E/I balance has been implicated as a
potential cause of behavioral phenotypes associated with ASD [
47]. Microglia, the phagocytic cells that
reside in the brain from the developmental period, engulf the synaptic
materials, thus pruning synapses and supporting synaptic maturation. [
48]. When microglial function is
compromised, improper synaptic pruning can disrupt the E/I balance and
potentially contribute to the pathogenesis of ASD [
49]. Notably, microglia exhibit sexually dimorphic
transcriptional and translational profiles [
50]. Furthermore, the morphology and number of microglia in the
developing rat brain differ between male and female rats [
51]. During the early postnatal period, male rats have
significantly higher numbers of microglia compared to female rats. These
sex-based differences in microglial numbers appear to be functionally related to
sex-specific behaviors [
52].
The contactin-associated protein 2 (
CNTNAP2) gene encodes the
CASPR2 protein, which is a neurexin-related synaptic cell adhesion molecule. A
study utilizing high-density single nucleotide polymorphisms identified
CNTNAP2 as a strong candidate gene implicated in the
etiology of ASD [
53]. Subsequent
loss-of-function studies in
Cntnap2 KO mice demonstrated that
the absence of
Cntnap2 leads to a decrease in dendritic spine
density [
54], disruptions in synaptic
function [
55], imbalances in E/I
signaling, and impaired neural oscillations [
56]. These
Cntnap2 KO mice also display core
ASD-like behavioral phenotypes, including impairments in sociability and
repetitive behaviors [
57]. Dawson et al.
found that male
Cntnap2 KO mice exhibited pronounced social
deficits, whereas their female counterparts did not. Further investigation into
the anterior cingulate cortex—a region critical for social behavior
regulation through its connections with other intracortical and subcortical
areas—revealed a more activated morphology and increased phagocytosis of
synaptic structures in male KO mice compared to WT mice, a distinction not
observed in female KO versus WT mice [
58].
In addition to genetic models, differences in microglial morphology and function
have been observed in preclinical models that incorporate environmental risk
factors. High levels of air pollution, particularly during development [
59,
60], and maternal stress (MS) during gestation [
61,
62] have been linked to an increased risk of ASD. Smith et al.
investigated the combined effects of these two risk factors and found that
prenatal exposure to air pollution—specifically diesel exhaust particles
(DEP)—along with MS in mice led to sociability deficits exclusively in
male offspring [
63]. These behavioral
impairments were paralleled by alterations in microglial morphology and gene
expression, with DEP/MS exposure resulting in a hyper-ramified microglial
phenotype in male but not female animals.
The collective evidence from these reports suggests that sexually dimorphic
microglial activity could play a role in the etiology of ASD. This activity may
disrupt the development of neural circuits responsible for social behavior by
excessively pruning synapses during a critical period of development [
49].
Sex steroid hormones are known to contribute to sex differences in neural
activity and behaviors in mammals through their interactions with specific
nuclear hormone receptors [
64].
Testosterone plays a crucial role during prenatal development in shaping sex
differences, influencing brain structure, neurotransmitter and receptor levels,
neurogenesis, immune responses, neuropeptide signaling, and cellular processes
such as apoptosis, migration, and differentiation [
65]. Clinical reports have correlated high levels of
testosterone with autistic behavior [
66,
67], and this association
is supported by Erdogan et al., who showed that prenatal testosterone exposure
led to ASD-like behaviors in the offspring of Wistar rats [
68]. Both male and female rats exposed to testosterone
exhibited reduced interaction times with a stranger rat during the three-chamber
sociability and social novelty test, indicating a decrease in social interaction
and a phenotype with characteristics resembling ASD. In line with these
findings, studies on the valproic acid (VPA)-induced ASD mouse model, which is
based on a medication known to increase the risk of ASD in humans [
69], have shown that elevated plasma
testosterone levels resulting from VPA treatment led to significantly lower
levels of tyrosine hydroxylase (TH) expression in the anteroventral
periventricular nucleus of male mice. In contrast, TH levels in female mice were
unaffected [
70].
Allopregnanolone (ALLO), a 3ɑ, 5ɑ progesterone metabolite [
71], is a key GABAergic neurosteroid [
72,
73]. Reduced ALLO levels are correlated with a greater severity of
restricted and repetitive behaviors [
74].
Penn and colleagues have shown that ALLO plays a vital role as a placental
hormone in shaping the fetal brain, leading to sexually dimorphic behavioral
outcomes [
75]. Specifically, a deficiency
of placental ALLO in mice resulted in male-specific abnormalities in cerebellar
white matter and core ASD symptoms, such as diminished social preference and
increased repetitive behaviors. Notably, this study observed sex-linked
dysregulation of myelin proteins in the cerebellar vermis of preterm infants,
which aligns with human data.
These results highlight the influence of hormones in molding the early brain
environment, potentially leading to sexually dimorphic behavioral outcomes.
Escape from X chromosome inactivation
In a mouse model of early prenatal stress, male offspring exposed to MS during
gestation exhibited certain NDD phenotypes [
76,
77]. The placenta plays a
critical role during pregnancy, acting as a mediator in response to disturbances
within the intrauterine environment [
78].
MS leads to sexually dimorphic changes in the placental expression of
O-linked-N-acetylglucosamine transferase (OGT), an X-linked gene essential for
the regulation of proteins involved in chromatin remodeling [
79]. Notably, OGT escapes X chromosome
inactivation in the placenta, resulting in placental levels that are
approximately twice as high in female animals than in male animals. Crucially,
this finding also translates to humans: levels of both OGT and its biochemical
marker, O-GlcNAcylation, have been found to be considerably lower for male
fetuses and are further reduced by prenatal stress [
79]. Nugent et al. demonstrated that OGT levels establish a
sex-specific gene expression pattern in trophoblasts through regulation of a
canonical histone repressive mark, H3K27me3 [
80]. Higher placental levels of H3K27me3 for female offspring
provided a protective effect against the altered hypothalamic programming
associated with prenatal stress exposure. Consequently, lower levels of OGT may
predispose male offspring to a higher risk of ASD. Future studies should explore
the molecular mechanisms underlying this increased male susceptibility.
Maternal immune activation (MIA) during pregnancy is linked to a heightened risk
of ASD in offspring [
81]. This phenomenon
has been extensively investigated using a rodent MIA model. In this model,
pregnant mice received intraperitoneal injections of polyinosinic:polycytidylic
acid (poly[I:C]), a synthetic analog of double-stranded RNA that simulates viral
infection. The offspring exhibited significant neurodevelopmental impairments,
including diminished social interaction and increased repetitive behaviors
[
82–
84]. Kalish et al. found that MIA exerts a sexually
dimorphic effect in utero, leading to different behavioral outcomes. Male
offspring exhibited MIA-induced behavioral abnormalities, whereas female
offspring did not [
85]. Notably, when
gene expression was examined at the single-cell level, changes in the fetal
cortex were observed to be sexually dimorphic. In male fetuses, these changes
were predominantly characterized by reduced gene expression related to protein
translation, followed by an overactive ISR pathway. In eukaryotic cells, the ISR
signaling pathway regulates protein synthesis in response to various stresses,
both physiological and pathological, to restore cellular homeostasis [
86]. Dysregulation of protein synthesis has
been implicated in ASD-related traits and other neurological disorders [
87–
89]. Male-specific activation of the ISR is dependent on the
maternal induction of interleukin (IL)-17A following MIA, which has been shown
to be necessary for the development of MIA-induced ASD-like behaviors in mouse
offspring [
83]. The genetic and
pharmacological inhibition of ISR pathway hyperactivation was sufficient to
protect male offspring from MIA-induced behavioral abnormalities. This study
offers valuable insights into potential preventative strategies for ASD-like
phenotypes that may result from prenatal immune activation.
Preterm delivery is associated with a higher likelihood of ASD in children
compared to those born at full term [
90–
93].
Chorioamnionitis, caused by Group B
Streptococcus (GBS;
Streptococcus agalactiae), is one of the most common
maternal infections and accounts for 40% to 70% of preterm births [
94–
96]. This condition typically involves an inflammatory intrauterine
environment, even in the absence of bacterial translocation from mother to fetus
[
97]. Allard et al. demonstrated that
prenatal infection with live GBS in rats resulted in social impairments in male
but not in female offspring [
98]. A
prominent inflammatory state was noted in male animals, with higher levels of
the pro-inflammatory cytokine IL-1β and the cytokine-induced neutrophil
chemoattractant-1 (CINC-1/CXCL1), compared to female rats. These findings
suggest that sex-specific inflammatory profiles may contribute to the observed
sexually dimorphic behavioral outcomes [
98].
Consistent with this notion, in a model of MIA induced by lipopolysaccharide
(LPS), a toll-like receptor 4 agonist, Braun et al. investigated sex-specific
pro-inflammatory responses in both the placenta and fetus, as well as their
effects on behavioral outcomes. Male offspring of mothers exposed to LPS
exhibited behavioral abnormalities in social interaction and learning, as well
as increased repetitive behavior, whereas female offspring were unaffected
[
99]. Male MIA offspring showed
increased cortical hypoxia, decreased mitosis of radial glial cells, and
disrupted E/I balance in the brain. Additionally, severe placental necrosis,
heightened inflammation, and reduced placental growth were specifically observed
in male mice affected by MIA, suggesting that unique sex-specific placental
characteristics may make male offspring more susceptible to intrauterine
disturbances.
Carlezon Jr et al. demonstrated sex-specific behavioral effects and immune
responses in the brain using a combined rodent “two-hit” immune
activation model. This model involved treatment with poly (I:C) to induce MIA
and the administration of LPS to produce postnatal immune activation [
100]. Exposure to early-life immune
activation (EIA) was shown to lead to reduced social interaction and increased
repetitive behaviors in male animals, while female rodents displayed no
significant changes. Molecular studies indicated that EIA resulted in pronounced
sex-specific alterations in the expression of inflammation-related genes in the
brain. Both male and female rodents exposed to EIA exhibited elevated levels of
pro-inflammatory factors in the brain, such as tumor necrosis factor alpha,
inducible nitric oxide synthase, IL-6, and IL-1β. Conversely, the
expression of anti-inflammatory factors like IL-10 and transforming growth
factor beta 1 was reduced in male mice but elevated in female animals [
100].
The collective findings of these studies suggest that sexually dimorphic
inflammatory responses could potentially contribute to the sex-specific effects
of MS on the neurobehavioral outcomes of offspring.
Discussion
Implication and suggestion
In this review, we have comprehensively examined the potential mechanisms by
which genetic variants and environmental factors contribute to sex differences,
as demonstrated by preclinical models. Our analysis encompassed both intrinsic
differences in the brain, such as synaptic connectivity and microglial activity,
and the potential influence of extrinsic factors, including sex hormones and the
placenta. These elements may either increase male susceptibility or bolster
female resilience. Notably, beyond the intrinsic factors of the brain, the
hormonal profile, epigenetic landscape, and immune pathways associated with the
placenta have been implicated in contributing to sexually dimorphic outcomes in
mouse models exhibiting ASD-like behaviors. This indicates that a deeper
understanding of the placenta as a temporary but dynamic interface during
prenatal development could provide valuable insights into the sex biases
observed in NDDs.
Although preclinical mouse models of ASD have important limitations, such as
their inability to engage neural circuitry comparable to that observed in humans
or to recapitulate all human ASD phenotypes [
8], they remain valuable tools for gaining mechanistic insights into
ASD pathogenesis and for developing potential therapeutic approaches [
10,
11]. Further investigation is imperative to unravel the mechanistic
basis of sexual dimorphism in ASD, as well as in other NDDs. For example,
utilizing large-scale transcriptomics from postmortem brain studies [
101], generating a single-cell atlas
[
102], and conducting multi-omic
profiling of somatic mutations [
103] in
brains exhibiting ASD could help uncover sex-specific changes in genes or
pathways during early neurodevelopment. Given that ASD is a developmental
disorder, it is crucial to conduct further longitudinal investigations to
understand how risk factors evolve across the developmental trajectory. For
instance, a longitudinal cohort study of children with developmental
disabilities suggested that
de novo protein-truncating variants
were correlated with clinical characteristics [
104].
Overall, understanding sex-specific mechanisms is pivotal for comprehending the
fundamental causes of ASD and may illuminate the pathologies of other diseases
characterized by prominent sex biases.
Authors' contributions
-
Project administration: not applicable
Conceptualization: Lee T, Kim E
Methodology & data curation: not applicable
Funding acquisition: Kim E
Writing – original draft: Lee T
Writing – review & editing: Lee T, Kim E
Conflict of interest
-
Eunha Kim serves as a consultant for Interon Laboratories.
Funding
-
Eunha Kim received support through a Korea University grant (K2225821).
Data availability
-
Not applicable.
Acknowledgments
We would like to express our gratitude to all members of the Kim laboratory for their
insightful comments. We also give special thanks to Hyun Je for providing technical
assistance in structuring the manuscript.
Supplementary materials
-
Not applicable.
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