The Dynamicity of the Oxytocin Receptor in the Brain May Trigger Sensory Deficits in Autism Spectrum Disorder

Abstract

Sensory processing abnormalities have been noted since the first clinical description of autism in 1940. However, it was not until the release of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) in 2013 that sensory challenges were considered as symptoms of autism spectrum disorder (ASD). Multisensory processing is of paramount importance in building a perceptual and cognitive representation of reality. For this reason, deficits in multisensory integration may be a characteristic of ASD. The neurohormone oxytocin (Oxt) is involved in the etiology of ASD, and there are several ongoing clinical trials regarding Oxt administration in ASD patients. Recent studies indicate that Oxt triggers muscle contraction modulating thermogenesis, while abnormal thermoregulation results in sensory deficits, as in ASD. Activation of the Oxt system through exposure to cold stress regulates the expression of oxytocin receptor (Oxtr) in the brain and circulating Oxt, and if this mechanism is pathologically disrupted, it can lead to sensory processing abnormalities since Oxt acts as a master gene that regulates thermogenesis. This review will describe the sensory deficits characteristic of ASD together with the recent theories regarding how the modulation of Oxt/Oxtr in the brain influences sensory processing in ASD.

Full text

Academic Editor: Tomasz Popławski
Received: 6 November 2024
Revised: 9 January 2025
Accepted: 10 January 2025
Published: 17 January 2025
Citation: Camerino, C. The
Dynamicity of the Oxytocin Receptor
in the Brain May Trigger Sensory
Deficits in Autism Spectrum Disorder.
Curr. Issues Mol. Biol. 2025,47, 61.
https://doi.org/10.3390/
cimb47010061
Copyright: © 2025 by the author.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
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(https://creativecommons.org/
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Review
The Dynamicity of the Oxytocin Receptor in the Brain May
Trigger Sensory Deficits in Autism Spectrum Disorder
Claudia Camerino 1,2
1Department of Precision and Regenerative Medicine, School of Medicine, University of Bari Aldo Moro,
P.za G. Cesare 11, 70100 Bari, Italy; ccamerino@libero.it
2
Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, P.le Aldo Moro 5,
00185 Rome, Italy
Abstract: Sensory processing abnormalities have been noted since the first clinical de-
scription of autism in 1940. However, it was not until the release of the fifth edition of
the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) in 2013 that sensory
challenges were considered as symptoms of autism spectrum disorder (ASD). Multisensory
processing is of paramount importance in building a perceptual and cognitive representa-
tion of reality. For this reason, deficits in multisensory integration may be a characteristic
of ASD. The neurohormone oxytocin (Oxt) is involved in the etiology of ASD, and there
are several ongoing clinical trials regarding Oxt administration in ASD patients. Recent
studies indicate that Oxt triggers muscle contraction modulating thermogenesis, while
abnormal thermoregulation results in sensory deficits, as in ASD. Activation of the Oxt
system through exposure to cold stress regulates the expression of oxytocin receptor (Oxtr)
in the brain and circulating Oxt, and if this mechanism is pathologically disrupted, it can
lead to sensory processing abnormalities since Oxt acts as a master gene that regulates
thermogenesis. This review will describe the sensory deficits characteristic of ASD together
with the recent theories regarding how the modulation of Oxt/Oxtr in the brain influences
sensory processing in ASD.
Keywords: oxytocin; oxytocin receptor; thermoregulation; autism spectrum disorder;
sensory processing; skeletal muscle; Diagnostic and Statistical Manual of Mental Disorders
(DSM-5)
1. Introduction
Autism is a complex neurodevelopmental condition and its cause is still unknown.
ASD is characterized by two main symptoms: persistent social communication and inter-
action difficulties and restrictive and repetitive behavior, interests and activities [
1
]. The
majority of research on autism spectrum disorder (ASD) has focused on social, commu-
nication and learning/cognitive challenges associated with the disease [
2
]. However, it
is only in the last 10 years that a new diagnostic criterion for ASD has been accepted by
the scientific community and included in the Diagnostic and Statistical Manual of Mental
Disorders (DSM-5): sensory processing [
3
]. Indeed, abnormalities in sensory processing can
influence behavioral and cognitive experience in ASD patients since alterations in social
cognition are marked by a very different perceptual experience of the world. Atypical
sensory experience is estimated in about 90% of ASD individuals in every sensory modality,
such as taste, touch, audition, smell and vision. The neurobiological alterations that affect
processes as diverse as cognition and sensory experience in ASD and the common thread
between them are still unclear. In order to begin to understand the disease, it is essential to
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Curr. Issues Mol. Biol. 2025,47, 61 2 of 13
clarify whether sensory difference represents secondary consequences after reduced social
interaction or sensory deficits influence both development and neurobiology. ASD affects
human experience from sensation to perception, to motor behavior and cognition. This is
why it is important to understand how these diverse domains can be related. Research on
sensory symptoms may help in simplifying this complexity by focusing on circuit-level
alterations in the brain that may affect cortical processing in ASD and offer translational
and pharmacological potential to cure this disease. Indeed, according to the “sensory-first”
theory, social/cognitive symptoms may be downstream effects of atypical sensory process-
ing in early development, while according to the “top-down” theory, symptoms relating
to sensation and social cognition might co-arise from alteration in attention or prolonged
lack of social interaction [
2
,
3
]. Perturbations in the inhibitory neurotransmitter gamma-
aminobutyric acid (GABA) receptor have been associated with autism, and GABAergic
signaling is disrupted in several different mouse models of autism [
2
,
3
]. Other neuromod-
ulators such as testosterone and oxytocin (Oxt) modulate GABAergic signaling and are
associated with autistic traits [
4
–
8
]. Oxt is a neurohypophysial hormone, as previously
described [
9
]. Oxt triggers skeletal muscle contraction through thermoregulation, and cold
stress exposure increases oxytocin receptor (Oxtr) expression in the brain and the Soleus
muscle (Sol), while it decreases circulating Oxt in mice, leading to what we have called
“The oxytonic effect” [
10
]. Oxt’s regulation of thermogenesis is linked to Prader–Willi
syndrome (PWS) and Schaaf–Yang syndrome (SYS) since both these pathologies present
increased circulating Oxt levels, muscle hypotonicity, decreased Oxtr expression in the
brain and frequent episodes of hypothermia and hyperpyrexia with no infection [
11
,
12
].
PWS and SYS patients also present a very high incidence of ASD [
13
] and they often present
a history of low body temperature and/or high body temperature with no apparent reason
provided on their medical history form [
12
]. PWS arises from the lack of expression of
paternally inherited genes on chromosome 15q11-q13 or maternal uniparental disomy or
an imprinting defect. Mage family member L2 (Magel2) is one of the affected genes located
on 15q11-q13 and mutations in Magel2 have been found in PWS, SYS and ASD individu-
als [
11
,
12
]. In a mouse model of autism in which Magel2 has been knocked down, Oxtr is
downregulated or upregulated according to postnatal Oxt treatment [
14
]. Magel2-KO mice
present neurodevelopmental impairment and autistic-like behavior [
12
]. In this review,
we explain the sensory deficits described in ASD in light of the novel theories that see
Oxt/Oxtr expression as being dynamically modulated in the brain, and we hope that these
results may be instrumental in designing precisely timed Oxt-based therapeutic strategies
that target specific brain regions and can improve the clinical features, both sensorial and
social, of ASD.
2. Autism and Sensory Deficits
In this section, we will describe some of the sensory deficits documented in ASD and
their manifestations (Table 1). Pediatric patients with ASD suffer hyper- or hyposensitivity
to visual, auditory, tactile and olfactory stimuli. ASD individuals also report paradoxical
heat sensations when cold is perceived as burning hot, indicating disruption of thermosen-
sory integration since central processing of information seems to be altered in ASD rather
than peripheral perceptions [
15
,
16
]. The existence of sensory abnormalities in ASD was
only recently included in the DSM-5 as diagnostic criteria for ASD (American Psychiatry
Association 2013) and have for a long time been overlooked [
15
]. Central mechanisms
during the integration of multisensory stimulus rather than peripheral mechanisms cause
sensory deficits in ASD. In the DSM-5, both hyper- and hypo-reactivity to sensory input
or unusual interest in sensory aspects or the external milieu are mentioned as diagnostic
criteria for ASD. These criteria include somatosensory abnormalities such as indifference to

Curr. Issues Mol. Biol. 2025,47, 61 3 of 13
pain related to temperature, adverse response to texture or excessive touching of objects
(APA 2013). For example, vibro-tactile stimulus perceived as static and poor vibro-tactile
amplitude discrimination have been reported in children with ASD [
16
]. Hypersensitivity
to thermal pain and innocuous thermal stimuli has been found in ASD in adults [
17
]. Con-
versely, adolescents with ASD showed normal detection of thermal pain but hyposensitivity
to innocuous thermal stimuli [
15
]. Moreover, in adolescents and adults with ASD, normal
pain detection was observed during thermal and electrical stimulation [
18
], where pressure
pain was also lower in children [
19
]. In a recent study, the somatosensory perception of
patients with ASD was investigated, since altered detection of somatosensory stimuli may
cause unusual sensory perception in ASD using the quantitative sensory testing (QST)
protocol on neuropathic pain. Hyper- or hyposensitivity to sensory inputs is normal in
certain parts of the body and abnormal in other parts, in line with the different innervation
from the many brain areas with peripheral and central neuronal activity. ASD patients
show similar thresholds in detecting innocuous warmth and cool and light pressure on
their palm and forearm, but hypersensitivity to vibrations was seen in ASD on the forearm
and hypersensitivity to thermal pain at both sites. Interestingly, individuals with ASD
exhibit enhanced perception of certain stimulus properties such as vision, where local,
circumscribed properties of a visual stimulus are seen instead of the complete picture. This
peculiarity of ASD is described as follows: “ASD individuals see the tree but not the forest”.
A similar pattern of perception is also present in the auditory domain where the change of
a single note of a melody is perceived to be stronger than global melodic changes [
20
]. That
sensory deficits in ASD vary according to the age of patients and the area of the body is an
important concept consistent with the plasticity of the Oxtr expression in the brain, as we
will explain in the following sections [13].
Table 1. In autism spectrum disorder, sensory deficits are present in all domains of sensorial experience.
Sensory Deficits in Autism Spectrum Disorder
Auditory
Enhanced auditory perception of details at the
expense of the global situation. For example,
hearing the change of a single note and not the
change of the entire melody.
Hyposensitivity and
hypersensitivity
in all domains.
Vision
Enhanced perception of certain stimulus
properties since circumscribed properties of a
visual stimulus are seen over the complete
picture. For example, seeing the tree and not the
forest.
Tactile
Sensorial experience changes according to the
part of the body, as pressure is perceived
normally on the palm of the hand and forearm,
while hypersensitivity to vibrations is reported
in the forearm only. Adverse response to texture
is reported where vibro-tactile stimulus was
generally perceived as static.
Thermoregulation
Paradoxical heat sensation is reported where
cold is perceived and burning hot and hypo- or
hypersensitivity to thermal innocuous thermal
stimuli is also reported according to the age of
the patients.
Prader–Willi syndrome individuals often present
autism spectrum disorder and hypothermia and
hyperpyrexia with no infection are reported.
3. Oxytocin and Sensory Deficits in Autism Spectrum Disorder
Oxt/Oxtr
−/−
mice have impaired thermoregulation, resulting in thermosensory
deficits and the inability to maintain a stable temperature [
21
,
22
]. Our previous stud-
ies indicate that temperature regulation is impaired in PWS individuals since they show

Curr. Issues Mol. Biol. 2025,47, 61 4 of 13
significant changes in thermoregulation compared to siblings or controls [
19
,
21
–
23
]. PWS is
caused by the loss of expression of a critical genetic region on chromosome 15q11-q13 and a
very high percent of PWS individuals also present ASD. Our studies also indicate that Oxt
acts as a master gene regulating thermogenesis and influences the manifestation of the PWS
phenotype [
9
,
13
]. A small but statistically significant proportion of PWS children have been
reported to experience persistent or episodic hyperpyrexia/hypothermia [
11
], whereas
fingertip temperature is unaltered [
22
,
24
,
25
]. About 90% of ASD individuals have a sensory
abnormality that manifests with hyper- and hypo-reactivity to smell, taste, audition, vision
and tactile sensitivity. The sensory deficit influences the perception of the external word and
social behavior [
26
]. Oxt is also released in response to tactile stimuli, and Oxt in the plasma
of autistic children is decreased compared to neurotypical individuals [
27
]. Abnormalities
in the gene that encodes for Oxtr [
28
] as well as in Oxt have been found in ASD [
29
]. This is
why we hypothesize that Oxt regulation of thermogenesis can cause sensory abnormalities
in ASD (Table 2). Moreover, children with ASD present altered thermal thresholds with
reduced sensitivity to warmth, coolness and heat, but not pain threshold. We speculated
that this evidence may be significant since ASD individuals, unlike PWS individuals, do
not have hypothalamic syndrome, which can per se cause temperature fluctuations and
sensory abnormalities. However, a more comprehensive study of ASD is not within the
scope of this article, which regards exclusively the relationship between ASD and sensory
deficits. Oxt’s regulation of thermogenesis may be responsible for sensorial functionality
and body temperature regulation through muscle contraction in healthy individuals, while
a dysfunctional Oxt system can cause varying degrees of sensory abnormalities and muscle
hypotonicity, as seen in PWS and ASD.
Table 2. Oxytocin and sensory deficits in autism spectrum disorder.
•Oxytocin is a master gene regulating thermogenesis.
•Oxytocin-deficient mice and oxytocin receptor-deficient mice have impaired
thermoregulation and inability to maintain a stable temperature.
•Oxytocin is released due to tactile stimuli.
•Autism spectrum disorder children are reported to have a lower oxytocin
concentration.
•
Autism spectrum disorder individuals are reported to have sensory deficits such as
paradoxical heat sensations, altered thermal threshold, and hyper- or
hypo-reactivity to smell, taste, audition, vision and tactile sensitivity.
•The altered sensorial perception in ASD individuals can cause the cognitive and
social dysfunction typical of this condition.
4. Oxytocin Receptor Modulation Is Dynamic Across Lifespan and Is
Sexually Dimorphic
Oxt levels are lower in autistic compared with neurotypical children; however, this
difference is not detectable in adults [
30
]. ASD is characterized by deficits in social inter-
action and communication and restricted interests together with sensory deficits (APA
2013). These traits are all thought to be mediated by Oxt. Indeed, several components
of the Oxt/Oxtr system have been associated with ASD. Variations in these genes can
affect Oxt/Oxtr expression and distribution. Some studies found Oxt levels to be inversely
correlated with ASD severity; however, the expression of Oxtr in the brain has not been
investigated. The fact that Oxt is lower in autistic children highlights an involvement of the
Oxt system in the development or manifestation of ASD [
28
]. From this perspective, the Oxt
system can shape the brain for social interaction and sensory perception during a critical pe-
riod in infancy during which there is probably a critical window when Oxt administration

Curr. Issues Mol. Biol. 2025,47, 61 5 of 13
may be effective. However, little is known about the developmental trajectory of Oxt/Oxtr
and the causality of these manifestations in ASD, which is why studies on the genetics of
Oxt/Oxtr are necessary. In this regard, thermoregulation may modulate Oxtr in the brain
and cause sensory deficits in ASD [
30
]. The experimental manipulation of Oxtr expression
levels and Oxtr gene KO can have a significative effect on behavior and physiology [
31
].
This can lead to the identification of a critical window of Oxtr expression in the brain
together with associated genes, which is important for understanding ASD and other psy-
chiatric illness. Oxt/Oxtr expression is dynamic throughout a person’s development, with
critical periods. Indeed, Oxtr peaks in early childhood and late adulthood and is highly
correlated with dopaminergic signaling across a lifespan to adapt to shifting environmental
challenges. The peak in Oxtr expression observed during early childhood is probably
stronger in males because it is influenced by gonadal steroids. These sex differences may
contribute to the reported sex differences in neurodevelopmental disorder diagnoses and is
consistent with the sex bias of ASD recurring more often in males than females. Specifically,
the early childhood peak of Oxtr binding that was observed in brain tissue of the ventral
pallidum tissue from neurotypical donors was absent in the same tissue in autistic donors.
Moreover, Oxtr expression and binding are higher in the ventral pallidum and nucleus
basalis of Meynert brain tissue of neurotypical donors than the same tissue of autistic
donors [
31
]. Oxtr undergoes epigenetic modifications, and these modifications predict
the severity of symptoms in adults with ASD. Indeed, the neural networks involved in
reward processing and social capability in ASD involve the Oxt/Oxtr system, which is
sensitive to epigenetic processes caused by environmental exposure, and these epigenetic
modifications account for the features of autistic traits. Specifically, Oxtr hypermethylation
in the intron 1 area of MT2 was related to a less severe developmental phenotype making
this site a potential biomarker of adults with ASD with less severe verbal communication
deficits [
32
]. It is worth noting that thermoregulation and thermogenesis can also cause
epigenetic modifications of Oxtr.
5. Current Theories Explaining Sensory Deficits in Autism
Spectrum Disorder
Individuals with ASD “See the trees but not the forest”, which means that ASD
individuals see the details of the perceptual world rather than the global picture [
30
].
To understand autistic sensory experience, the perceptual processing cannot be simply
characterized as a talent or a deficit reflecting neither hyposensitivity nor hypersensitivity,
but sensory experience in ASD exhibits a bias toward local versus global characteristics
of a sensory scene which can be more or less advantageous according to the task [
2
].
Moreover, these sensory processing abnormalities also impact other domains of ASD such
as social communications, worsening their severity [
3
]. This is why individuals with
ASD have enhanced performance in tasks that rely on the analysis of stimulus details but
have difficulties when these details need to be integrated into a complete image. Sensory
difference is a common issue in ASD and much of our cognitive and social representations
are dependent upon sensory inputs. In this regard, there are at least five theories that
explain the ASD. The first theory, also called “Theory of mind” [
33
], suggests that ASD
individuals have a decreased ability to understand other people’s feelings and this can be
caused by abnormalities in sensory processing. Neuroimaging studies reveal that inferior
frontal regions including the mirror neuron system and the temporoparietal junction are
involved in these tasks. The second theory, named “Weak central coherence” [
34
], proposes
that the meaning of things is built through the integration of information across lower-level
sensory and higher-level cognitive processing, and this is abnormal in ASD individuals.
The classic illustration of how this theory works is that to understand a complex visual

Curr. Issues Mol. Biol. 2025,47, 61 6 of 13
scene, the integration of all details is necessary and not focusing on single details, as seen
in the tree and forest example. The third theory is named “Predictive coding hypothesis”
and is based on the notion that individuals with ASD do not have a robust historical
representation of the world, making it difficult for them to predict upcoming events and
limiting interactions with external environments. This explains, for example, the tendency
of ASD individuals to engage in repetitive behavior to limit novel sensory inputs in an
endlessly novel world [
35
]. The fourth theory is called “Reduced sensory precision and
reliability” and states that changes in the variability of neural response patterns create
variability (or less reliability) in their behaviors and perceptions [
36
]. Finally, the fifth
and last theory is based on evidence that GABA functioning is altered in ASD, leading to
increased excitation for greater glutamatergic signaling, while inhibition is decreased for
less GABAergic signaling. Indeed, glutamate and GABA signaling are involved in cortical
function, including sensory processing and social function. In this context, increased
excitability may explain hypersensitivity in sensory processing, with sensory input eliciting
an abnormally large cortical response that makes the experience overwhelming [
4
–
7
,
9
,
36
].
This theory has been confirmed by a recent study on animal models [
37
]. However, here,
we propose a novel theory according to which the sensory deficits in ASD can be triggered
by the differential modulation of Oxtr in the brain, as we explain in the following sections.
6. Oxytocin and Oxytocin Receptor Expression Modulation in the Brain
May Trigger Sensory Deficits in Autism Spectrum Disorder:
New Theories
In this section, we will describe the most recent studies regarding the modulation of
Oxtr in the brain and how it can impact sensory deficits in ASD. In particular, we will focus
on four recent studies focusing on the Oxt/Oxtr system.
6.1. Oxytocin Is a Master Gene That Regulates Thermogenesis, and Cold Stress Modulates
Oxytocin Receptor in the Brain and Peripheral Oxytocin
The first study [
10
] shows that Oxt is anabolic in muscle, and Oxt anti-obesogenic
effects are also related to its positive effects on muscle mass. We characterized Oxt and
Oxtr expression in different tissues after a cold stress (CS) challenge in mice by an
in vivo
approach. In this study, a cold stress protocol was elaborated and mice were kept at 4
◦
C
for either 6 h or 5 days. Then, mice were sacrificed and properly dissected. Blood was
collected and brains were quickly extracted, snap-frozen and analyzed by histomorphome-
try as previously shown [
10
]. Mice initially lost body weight, but after 5 days these mice
regained their body weight, indicating that they were in good health. The exposure to
cold stress activates shivering thermogenesis. In this regard, we hypothesize that there is
a feedback loop between the hypothalamus and muscle that regulates the rate of central
Oxt release and Oxtr expression level in the brain together with muscular Oxtr expression.
This feedback loop between the brain and muscle is activated in response to situations
requiring increased musculoskeletal performance such in shivering thermogenesis [
11
,
13
].
We showed in mice that Oxtr expression increases in the Soleus (Sol) muscle and in the
brain after the CS challenge, while circulating Oxt decreases [
10
]. The dynamicity of Oxtr
following a thermogenic challenge can trigger sensory deficits in ASD since Oxt regu-
lates thermogenesis (Table 3). The cold stress model is explained in Table 3and has been
previously published [10].

Curr. Issues Mol. Biol. 2025,47, 61 7 of 13
Table 3. Ex vivo study of oxytocin and oxytocin receptor expression in the brain after expo-
sure to 6 h or 5 days of cold stress in wild-type mice and measurement of circulating oxytocin.
“
−
” indicates a significative decrease compared to untreated control; “+” indicates a significative in-
crease compared to untreated control. Cold stress increases Oxtr in Paraventricular and Supraoptical
Nuclei of hypothalamus and decreases circulating Oxt in a feed-back/feed-forward loop with the
brain [10].
Ex vivo Studies
Oxt 6 h Oxtr 6 h Oxt 5 d Oxtr 5 d
Hippocampus * * * −
Hypothalamus * * * *
Paraventricular Nucleus * + * +
Supraoptical Nucleus * + * +
Circulating Oxytocin Decreases
* no changes detected.
6.2. Oxytocin Receptor Expression Is Dynamic and Is Normalized by Oxytocin During a Specific
Temporal Window
The second study [
14
] reports that Magel2 is a gene included in the PWS locus [
38
],
and in addition to many pathological PWS phenotypic traits, the syndrome presents a high
incidence of ASD [
39
]. Magel2-KO mice recapitulate autistic traits and neurodevelopmental
impairments. In this study, three to five hours after delivery, pups were subcutaneously
injected with saline or Oxt, and this administration was repeated every 2 days. Then, 8 days
after birth or 90 days after birth, mice were sacrificed, the brains were extracted and Oxtr
was quantified as described [
14
]. An ultrasonic microphone was used to record the pups’
vocalization. The aim of this study was to extend the regional mapping of Oxtr in male
and female Magel2-KO brains with or without Oxt treatment. This is important because
Oxt is strongly regulated in the first week of life in mice, and understanding the specific
site of action of Oxt in the brain and the specific window of time when it is effective will
be essential to design a therapy with Oxt for ASD. Moreover, Oxtr is sexually dimorphic,
which is why Oxtr was differently modulated according to gender after treatment with Oxt.
Early postnatal Oxt treatment prevents neonatal lethality in these mice and prevents
social and learning deficits in adult Magel2-KO mice [
40
]. Indeed, region-specific alterations
in Oxtr expression are present in Magel2-KO mice, and postnatal Oxt treatment could
modulate Oxtr in specific brain regions. In Magel2-KO pups characterized by deficient
production of hypothalamic Oxt [
38
], the neuropeptide may be unable to play its role as a
mediator of early sensory functions, and the postnatal supplementation of Oxt may restore
this function [
14
]. The action of Oxt in the brain is mediated by Oxt binding to Oxtr [
39
].
Environmental factors during early infancy can epigenetically modify the Oxtr gene and
influence its expression level in adulthood [
40
]. Early modulation of Oxtr expression is
important in neurodevelopmental disorders with social and cognitive deficits, as in ASD.
Indeed, several mouse models of neurodevelopmental disorders present deficits in Oxt or
Oxtr expression [
41
]. Oxtr is strongly regulated in the first three weeks of life in mice [
42
].
A recent study investigated whether Oxt treatment received in the first weeks of life had
short- or long-term effects on regional Oxtr expression and if it is gender specific, since ASD
had a higher incidence in males than in females [
14
]. Indeed, the Oxt system is sexually
dimorphic [
43
]; for example, in humans, following a social stress test, a single dose of
intranasal Oxt increases distress and anger in women but reduces distress in men [
44
].
Magel2-KO mice show highly variable region-specific patterns of Oxtr expression that
vary according to Oxt administration, age and gender. Indeed, at post-natal day 8 (P8)

Curr. Issues Mol. Biol. 2025,47, 61 8 of 13
Magel2-KO mice show a significant reduction in Oxtr levels in the brain compared to
controls, indicating a major defect in Oxtr expression in the brain. This defect is present
in males and females, and is not removed by the treatment with Oxt [
14
]. On the other
hand, in Magel2-KO mice at P90, Oxt treatment normalizes Oxtr expression, specifically in
those regions of the brain where Oxtr is abnormally upregulated compared to the control,
such as the amygdala and hippocampus and piriform cortex, indicating an impaired
developmental pattern of Oxtr expression. This effect was more evident in male mice than
in female mice, which is consistent with the well-recognized sex bias in ASD incidence.
One possible explanation is the existence of a temporal window in which these regions
of brain are particularly sensitive to Oxt, since during neurodevelopment, brain circuits
mature at different times and Oxt modulates sensory inputs and shapes brain circuits and
connectivity. Conversely, when the Oxt system is defective, sensory inputs are defective
or absent, failing to shape mature brain circuits. A similar time window was observed
during a clinical trial with Oxt in PWS infants where Oxt administration prevents the
failure to thrive of these infants only before 6 months of age [
45
]. The same results after
Oxt administration were not detectable at any other age considered.
6.3. The Oxytocin System Requires Both Oxytocin/Oxytocin Receptor Expression and Synaptic
Excitation/Inhibition Trasmission
The third study [46] shows that in the absence of Magel2, overall ex vivo Oxt neuron
activity is suppressed for altered synaptic input profile resulting from decreased excita-
tory and increased inhibitory currents in mice. This shows that perturbations of the Oxt
system include both neuropeptide expression [
13
,
20
] and inhibitory/excitatory synaptic
transmission [
46
]. However, while the studies described above [
13
,
20
] rely on peptide
or mRNA expression level measurement, Oxt is a signaling molecule that functions in a
broader circuit of signaling and is dependent upon other hormones such as estrogens. For
this reason, in a Magel2-KO mouse model, synaptic and cell autonomous properties of
Oxt neurons were investigated. Magel2-KO mice were injected stereotaxically with Oxt
and voltage clamp recording was performed as described [
46
]. Indeed, the Oxt system
works through both Oxt expressing neurons and their connection and the expression of Oxt
and Oxtr. The combined addition of synaptic blockers for GABAergic and glutamatergic
transmission reduced the synaptic activity of Oxt neurons in control but not in Magel2-KO
mice, and this indicates a loss of excitatory drive in these mice [
46
]. These results are
consistent with previous studies on the involvement of GABA transmission in sensory
deficits of ASD [
2
,
3
]. So despite the restoration of Oxt levels in ASD, Oxt neuron defects at
circuit level persists, meaning that Magel2 deficiency permanently alters these circuits and
the constant presence of Magel2 is essential for Oxt circuit function [37].
6.4. Hypothalamic Gray Matter Volume and Concentration Are Reduced in Autism Spectrum
Disorder and Are Positively Associated with Peripheral Oxytocin
Finally, the fourth study [
47
] describes how the structural characteristics of the hy-
pothalamus produce different results between ASD and neurotypical controls in human
patients with a reduced gray matter volume or concentration in ASD children or adoles-
cence compared with healthy controls of corresponding age. The study [
47
] is particularly
relevant since it translates research from a mouse model to human patients. ASD individu-
als met DSM-5 criteria for autism and were diagnosed in accordance with current guidelines.
In this study, Oxt was measured in blood samples obtained exclusively at rest to rule out
any effect of Oxt on muscle contraction in ASD individuals [
48
]. Structural brain scans were
obtained and images were processed and analyzed using voxel-based morphometry as
described [
47
]. Notably, healthy carriers of Oxtr variants were associated with an increased
likelihood of ASD, displaying a significant decrease in gray matter volume in the hypotha-

Curr. Issues Mol. Biol. 2025,47, 61 9 of 13
lamus [
49
]. In a recent study, the morphological characteristics of the hypothalamus and
their relationship with Oxt in ASD patients were analyzed through a region-of-interest
analysis using voxel-based morphometry [
37
]. The aim of the study was to determine if
there are differences in hypothalamic volume between autistic and neurotypical adults, if
differences in the Oxt system in ASD were reflected in the hypothalamic structure and if
these differences could be attributed to Oxt. To achieve this, the authors compared the gray
matter volume between autistic and non-autistic control groups; then, they compared the
differences in the relationship between hypothalamic gray matter volume and peripheral
Oxt, and last, they analyzed the association between hypothalamic gray matter volume
and ASD quotient scores as a measure of autistic traits [
37
]. Hypothalamic gray matter
volume does not change between autistic and non-autistic individuals; however, compar-
ing the group differences in terms of hypothalamic gray matter volume and peripheral
Oxt, a positive association was found in the ASD group and a negative association in the
non-autistic group. Hypothalamic gray matter volume was also associated with the autistic
group [
50
]. Basal concentration of Oxt is reported to be lower in autistic children [
31
,
48
]
but this difference disappears in autistic adults because of developmental changes in the
Oxt system in ASD. The importance of these developmental effects has also been shown for
Oxtr expression patterns [
31
]. This means that Oxt and Oxtr levels are dynamic and may
normalize with age in ASD, translating into normalization of gray matter volume. This
also means that the structural properties of the hypothalamus are related to Oxt levels in
ASD [
47
]. This is consistent with the concept of a time window in which the treatment with
Oxt is effective [
51
]. The most important changes in the hypothalamus and Oxt may all be
modulated by variations in Oxtr expression [
50
]. Gray matter volume seems to increase
alongside the increase in autistic traits, and this finding is probably caused by abnormalities
in the Oxt system and Oxtr expression levels. These results show that the increase in Oxt
levels can be caused by variations in Oxtr in the brains of ASD individuals, as seen after the
cold stress challenge [
13
,
51
]. Overall, the studies described above [
13
,
20
,
47
,
48
] are consis-
tent with the concept that Oxtr expression in the brain is dynamic and highly regulated by
factors such as thermogenic challenge and muscle contraction [
10
], the temporal window of
Oxt administration, sexual dimorphism and reproductive stage [
14
]. The integrity of synap-
tic transmission [
46
] and the feed-back between the brain and circulating Oxt [
13
,
48
] are
also important. These data, together with the evidence that Oxt is a master gene regulating
thermogenesis, made us hypothesize that the dysfunctional Oxt system could trigger sen-
sory deficits in ASD. A role for hypothalamic hormones in sensorial functions has also been
recently seen for gonadotropin-releasing hormone (GnRH) for olfactory function, consistent
with our data on Oxt [
52
,
53
]. Indeed, the integrity of the Oxt system and the expression
of Oxtr is essential to maintain the homeostasis of the body. This is evident, for example,
in mental illnesses such as eating disorders (ED) where ED-related Oxtr haplotypes alter
the relationship between proteins important for ED such as TGF-beta and sterol regulatory
element-binding proteins (SREBPs) and Oxtr expression. Such disruptions cause the failure
of compensatory Oxt-dependent mechanisms that would protect against starvation and
stress contributing to ED [
52
]. Oxtr expression in the brain is directly regulated by the
intake of carbohydrates and lipids [
54
,
55
], proving the dynamicity of Oxtr expression in
the brain. The most recent theories explaining ASD are shown in Table 4.

Curr. Issues Mol. Biol. 2025,47, 61 10 of 13
Table 4. Most recent theories explaining autism spectrum disorder.
Theory of mind
Suggests that ASD individuals have a decreased ability to
understand other people’s feelings and this can be caused
by abnormalities in sensory processing.
Weak central
coherence
Proposes that the meaning of things is built through the
integration of information across lower-level sensory and
higher-level cognitive processing and this is abnormal in
ASD individuals [34].
Predictive coding
hypothesis
Is based on the notion that individuals with ASD do not
have a robust historical representation of the world,
making it difficult for them to predict upcoming events
and limiting interactions with external environments.
Reduced sensory precision
and reliability
States that changes in variability of neural response
pattern create variability (or less reliability) in their
behaviors and perceptions.
Altered GABAergic
signaling
Theory is based on evidence that the imbalance in
excitatory and inhibitory processes is changed in ASD
with increased excitation for greater glutamatergic
signaling, while inhibition is decreased for less
GABAergic signaling.
Dynamicity of
oxytocin receptor
expression in the brain
The variation in oxytocin receptor expression levels may
cause sensory deficits, deficits in social
interaction/communication and restrictive interests in
autism spectrum disorder.
7. Conclusions
Developmental changes can influence the structure of the hypothalamus and the
expression of Oxt/Oxtr, triggering sensory deficits typically seen in autism. The action of
Oxt in the brain is mediated by Oxt binding to its specific receptor Oxtr, which is a G-protein-
coupled receptor expressed in several areas of the brain. An important feature of Oxtr is the
variability of its distribution in the different areas of the brain and it can vary according to
gender, age, pathological conditions and environmental factors [
11
,
20
]. The distribution of
Oxtr in the brain varies in mammals, consistent with social behavior and sexual dimorphism.
Moreover, Oxtr can undergo epigenetic modifications since early life experience has long-
term effects on the Oxt system and expression of Oxtr. Early life Oxt exposure may
influence life-long Oxtr expression, a theory known as “hormonal imprinting”, and it is
important in neurodevelopmental disorders characterized by social abilities since many
animal models of neurodevelopmental disorders present abnormalities in Oxt release and
Oxtr distributions [
41
,
44
,
47
]. Oxt regulates thermogenesis [
10
,
13
]. Indeed, the Oxt/Oxtr
system in a healthy brain is activated after thermogenic challenge, while a dysfunctional
Oxt/Oxtr system in the brain may trigger sensory deficits in ASD [
11
,
13
]. In this regard,
there may exist a time window for Oxt administration in ASD during which Oxt treatment is
effective. Future studies are necessary to prove this preliminary evidence. It is worth noting
that environmental factors may cause epigenetic modifications of the Oxtr expression in the
brain, as described for thermogenic challenge, altering Oxtr expression levels in the brain,
which can trigger sensory deficits in ASD. The Oxtr expression is dynamic and influenced
by epigenetic factors, reproductive stage and even nutrition. This is why a limitation of
this study that needs to be acknowledged is the challenge of translating animal models to
human patients. Indeed, progress in the biological detection and pharmacological treatment
of ASD has been limited for three main reasons. First, there were difficulties in obtaining
brain-related biological samples such as brain and cerebrospinal fluid from patients with

Curr. Issues Mol. Biol. 2025,47, 61 11 of 13
ASD. Second, the studies on ASD were performed on an animal model that lacked the
sophisticated social and cognitive abilities disrupted in ASD. Third, the primate species
used as a model for ASD still have several limitations [
1
,
55
,
56
]. We hope that the novel
perspective provided in this article can add new knowledge to the understanding of ASD.
Funding: This research was supported by the Grant “Ateneo 2017” from the University of Bari “Aldo
Moro” granted to Prof. Claudia Camerino.
Institutional Review Board Statement: This study was conducted according to the guidelines of the
Declaration of Helsinki and approved by the committee Organization for Animal Health O.P.B.A. of
the University of Bari on 21 January 2019 and by the Italian Minister of Health aut. N 665/2019 PR.
Conflicts of Interest: The author declares no conflicts of interest.
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