A comprehensive search was performed in the Web of Science database, PubMed, in November 2025, using keywords aligned with the study objectives: “autism,” “ASD,” “sport,” “exercise,” “physical activity,” “exercise intervention,” and “mechanism.” The following search strategy was constructed: ((autism OR ASD) AND (sport OR exercise OR physical)) AND (mechanism). A total of 2006 articles were retrieved.

The inclusion criteria were as follows (1): the study population consisted of individuals diagnosed with ASD (2); the study involved an exercise-based intervention; (3) the research focused on physiological mechanisms related to exercise and ASD; (4) the intervention procedures and study outcomes were clearly described; (5) the article was indexed in academic databases.

The exclusion criteria included: (1) non–peer-reviewed publications, such as editorials, conference abstracts, or dissertations; (2) articles not published in English.

After conducting the search, the authors independently screened the retrieved studies to assess whether they met the eligibility criteria. Studies lacking sufficient information were subjected to full-text review to confirm their inclusion. Two authors independently evaluated the studies based on the predetermined inclusion and exclusion criteria. Subsequently, the authors jointly reviewed the selected studies until a consensus was reached regarding their inclusion.After removing duplicate records, a total of 1,580 articles remained. Screening of titles and abstracts resulted in the exclusion of 1,159 articles. Full-text assessments were then conducted to determine eligibility, and the reference lists of the included studies were additionally examined to identify further relevant publications. Ultimately, 65 studies met the inclusion criteria. A flow diagram summarizing the study selection process is provided in Figure 1.

BDNF is a critical neurotrophin primarily expressed in the hippocampus. Once synthesized and secreted, BDNF regulates enzymatic activity via dendritic mechanisms. These processes, in turn, influence synaptic development, plasticity, and neuronal growth. An et al. examined the role of the long 3′ untranslated region (UTR) in the dendritic targeting of BDNF mRNA using a mouse mutant selectively expressing the long 3′ UTR of BDNF mRNA (21). Mice deficient in this long 3′ UTR variant exhibited impaired dendritic localization, resulting in diminished synaptic plasticity in hippocampal neurons. These findings suggest that dendritic synthesis and secretion of BDNF are essential for synaptic plasticity, and that deficits in BDNF signaling impair synaptic development and neuronal growth, suggesting a potential molecular mechanism underlying the pathogenesis of ASD.

Exercise has been shown to improve cognitive flexibility and motor function and to alleviate ASD-related symptoms. These effects are mediated by regulating BDNF expression, which activates the BDNF/TrkB signaling pathway and its downstream cascades and modifies astrocyte morphology (19–23). Studies have shown that four weeks of moderate-intensity aerobic exercise—five sessions per week, 30 minutes per session (10 min at 8.3 cm/s, 10 min at 13.3 cm/s, and 10 min at 26.6 cm/s)—enhances hippocampal BDNF and IL-6 levels, as well as skeletal muscle antioxidant enzymes, thereby improving cognitive flexibility and motor function in ASD model rats (19). Furthermore, emerging evidence indicates that 30 days of voluntary aerobic exercise, performed without forced intervention to avoid stress-induced effects on BDNF levels, can similarly confer beneficial effects. Induced elevation of BDNF levels may be mediated by the release of endogenous histone deacetylase (HDAC) inhibitors triggered by exercise. Aerobic exercise alters hepatic metabolism, facilitating the transport of the ketone body D-β-hydroxybutyrate (DBHB) through the bloodstream to the brain, where it functions as a class I HDAC inhibitor in the hippocampus, particularly targeting HDAC2 and HDAC3. Treatment of primary neurons with DBHB reduces the binding of HDAC2 and HDAC3 to the BDNF promoter, thereby increasing BDNF expression (22). Additionally, exercise mitigates ASD related symptoms by modulating the BDNF/TrkB signaling pathway (23). Following its expression and secretion, BDNF binds to its high-affinity receptor, TrkB, a tyrosine kinase receptor containing multiple tyrosine residues within its intracellular domain. Phosphorylation of TrkB subsequently initiates several key intracellular signaling cascades, including the mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, the phosphoinositide 3-kinase (PI3K) pathway, and the phospholipase C (PLC) pathway (24). (Figure 2).

The neurexin (NRXN) family, encoded by the homologous genes NRXN1, NRXN2, and NRXN3, constitutes a group of presynaptic transmembrane proteins. Each gene gives rise to two principal isoforms: the longer α-neurexins and the shorter β-neurexins, which are transcribed from alternative promoters. Further diversity within the NRXN repertoire is generated through alternative splicing (AS) of both isoforms, resulting in the production of more than a thousand distinct splice variants. Owing to the presence of multiple alternatively spliced exons across all three NRXN genes, a vast array of isoform diversity is achieved. All α-NRXNs undergo alternative splicing at six canonical splice sites (SS1–SS6), while β-NRXNs are limited to splicing at SS4 and SS5. The resulting splice variants exhibit selective affinities for a broad range of postsynaptic ligands, contributing to the regulation of synaptic specification, plasticity, and strength. Notably, inclusion of exon SS4 leads to the SS4⁺ variant, incorporating a 30-amino-acid insertion, whereas exon skipping yields the SS4⁻ variant. The presence or absence of this exon critically determines the binding specificity of neurexins to distinct postsynaptic molecules, thereby enhancing synaptic differentiation, plasticity, and specificity, as well as behavioral traits. These mechanisms are believed to underlie the potential amelioration of cognitive deficits observed in individuals with ASD (26).

Exercise can promote NRXN1–3 expression at alternative splice site 4 (SS4), thereby increasing the abundance of SS4⁺ splice variants in the prefrontal cortex and enhancing synaptic differentiation, plasticity, and specificity, ultimately contributing to the alleviation of ASD-related symptoms (25, 26). In support of this mechanism, a 12-week progressive aerobic exercise program—performed three times per week with treadmill speed gradually increased from 10 to 32 revolutions per minute (RPM)—has been shown to upregulate both the α- and β-isoforms of NRXN1–3 at SS4, thereby increasing the abundance of SS4⁺ splice variants in the prefrontal cortex (26). Notably, this effect was not observed in the hippocampus, likely due to greater molecular sensitivity and structural plasticity in the prefrontal cortex compared to the hippocampal region. Using splice site–specific primers, researchers detected significant exercise induced alternative splicing changes at SS4 of NRXN1–3 exclusively in the prefrontal cortex following continuous progressive exercise. These findings were further corroborated by quantitative PCR (qPCR), which confirmed an upregulation of SS4⁺ splice variants across all NRXN genes in the frontal cortex of continuous progressive trained mice (27).

Autistic individuals exhibit numerous abnormalities in their neurotransmitter systems, including serotonin, GABA, glutamate, dopamine, opioids, and oxytocin, with serotonin being the most significant. Serotonin, also known as 5-hydroxytryptamine (5-HT), plays a crucial role in brain development and alleviating ASD through the regulation of trophic factors (28). For example, 5-HT1A mediates the release of BDNF, which subsequently alleviates ASD. Serotonin is primarily produced by enterochromaffin cells and plays a pivotal role in secretion, sensation, and signal transduction within the body. It is a key signaling molecule in the “microbiota-gut-brain axis” and can also influence CNS microglial cells, thereby affecting mood and behavior in individuals (29).

The role of 5-HT, commonly known as serotonin, in ASD has been extensively documented. Empirical evidence suggests that repetitive behaviors, stereotyped movements, and deficits in social interaction—core features of ASD—are regulated by 5-HT signaling (30). This signaling involves the release of serotonin from neuronal vesicles into the synaptic cleft and extracellular space, where it binds to 5-HT receptors, including both heteroreceptors and autoreceptors (31). Following the release of 5-HT, the primary regulatory mechanism controlling extracellular 5-HT levels is the reuptake mediated by transporters, among which the 5-HT transporter (SERT) exhibits the highest affinity for 5-HT. During early development, 5-HT, through its interactions with enzymes, receptors, and transporters, coordinates essential neuronal processes, including cell division, differentiation, migration, and synaptogenesis, playing a pivotal role in the proper patterning and organization of sensory cortical neurons. Evidence from both human and rodent studies suggests that alterations in the synthesis, release, signaling, uptake, or metabolism of 5-HT can lead to dysregulated serotonergic activity, which may contribute to the risk or severity of ASD symptoms (32). Additionally, as one of the precursors of 5-HT, the level of tryptophan (TRP) has been shown to directly influence serotonin levels in the central nervous system (CNS) (33).

Exercise has been shown to increase levels of 5-HT in the CNS across species. This elevation is influenced by several factors, including increased levels of L-tryptophan, enhanced presynaptic 5-HT release, and reduced activity of monoamine oxidase (MAO), the enzyme responsible for the breakdown of monoamines in the synaptic cleft (34). A 4-week aerobic exercise regimen—performed once daily for 30 minutes with progressively increasing intensity (5 to 15 m/min, treadmill incline 0°)—can further enhance serotonin synthesis by activating tryptophan hydroxylase (TPH), a rate-limiting enzyme in serotonin biosynthesis, and by stimulating serotonin 1A (5-HT₁A) receptors, thereby ameliorating ASD-related symptoms (35). Studies have shown that two weeks of moderate-intensity aerobic exercise, performed for 20 minutes per day, exerts protective effects on vascular and neural function in rats, whereas high-intensity exercise downregulates neurotrophins and disrupts the expression of cell cycle–related proteins. In contrast, low-to-moderate–intensity aerobic exercise elevates 5-HT levels, modulates GABA and glutamate concentrations to maintain excitatory–inhibitory balance, and reduces the expression of inflammatory cytokines such as TNF-α, IL-1β, and IL-6, collectively contributing to the improvement of ASD-related symptoms (36). Moreover, aerobic exercise increases plasma concentrations of free fatty acids, which bind to albumin and displace TRP from its binding sites. Since the uptake of TRP by the brain and other organs primarily depends on the proportion of free (unbound) TRP, it is hypothesized that a higher fraction of free TRP crosses the blood–brain barrier (BBB), thereby enhancing cerebral serotonin synthesis (37, 38).

Growing evidence suggests that glial cells in the brains of individuals with ASD play pivotal roles in the progression and prognosis of the disorder. These cells interact dynamically with neurons via both chemical signals (e.g., neurotransmitters, neurotrophic factors, and cytokines) and physical mechanisms (e.g., gap junctions), thereby maintaining and modulating neuronal function. Consequently, glial cells function not only as key modulators of neuronal activity during brain development, but also as critical regulators of disease pathophysiology (39).

Astrocytes, the most abundant glial cells in the brain, are essential for supporting neuronal function during development. They regulate synaptic neurotransmitter levels by modulating dendritic spine formation and neuronal migration, thereby facilitating synaptogenesis and maintaining synaptic integrity. In ASD, astrocytic dysfunction may disrupt neurotransmitter metabolism and impair synapse formation. Consequently, alterations in astrocyte number or function may underlie the connectivity deficits commonly observed in individuals with ASD (40). Microglia, the brain’s resident immune cells, contribute to neurodevelopment, synaptic plasticity, and cognitive function. In ASD, elevated mitochondrial DNA (mtDNA) in serum extracellular vesicles has been shown to activate human microglia, leading to the release of the proinflammatory cytokine interleukin-1β (IL-1β) (41). Neuroimaging studies in individuals with ASD have demonstrated widespread microglial activation across multiple brain regions. Given that IL-1β impairs synaptic plasticity and neurogenesis, such immune activation may contribute to the emergence of stereotyped behaviors and cognitive deficits in ASD.

Exercise can elevate the expression of fibroblast growth factors (FGFs) and nerve growth factor (NGF), activate the mTOR signaling pathway in astrocytes, regulate microglial activation, and increase astrocyte density, thereby improving brain functions such as learning and memory and normalizing microglial metabolism and function, ultimately alleviating ASD-related symptoms (42–48). Studies show that a 4-week light-to-moderate aerobic exercise program—performed five times per week, 30 minutes per session, with a speed of 4–6 m/min—can increase astrocyte density in mice (42). This elevation has been linked to higher levels of exercise-induced FGFs and NGF (43, 44), both of which are known to promote astrocyte proliferation (45, 46). Lloyd et al. conducted a 6-week aerobic exercise program, performed five times per week for 12 hours per session, with running speed not exceeding 17 m/min, an average running bout duration of 2.04 ± 1.95 minutes, and inter-bout rest periods ranging from 0.33 to 30 minutes. They demonstrated that aerobic exercise enhances mTOR signaling in astrocytes, which is critical for brain functions such as learning, memory, cell growth, proliferation, and survival (47) (Figure 3). Moreover, a 10-day aerobic exercise program, starting at 25 minutes and increasing by 5 minutes every two days, performed at moderate intensity (first 5 minutes at 6.2 m/min, next 10 minutes at 8.2 m/min, followed by 10–15 minutes at 9.2 m/min, then 5–10 minutes at 10.2 m/min, and the final 5 minutes at 11.2 m/min, treadmill incline 0°), can modulate microglial activation (48). This effect reduces age related increases in hippocampal interleukin-1β (IL-1β) and helps alleviate ASD related symptoms (49). In this study, older sedentary mice expressed elevated levels of microglial markers, whereas exercise significantly decreased their expression. These findings suggest that exercise associated cognitive improvements may result from the normalization of microglial metabolism and function.

ASD is a neurodevelopmental condition of the CNS that typically emerges in early childhood. Growing evidence suggests that alterations in the gut microbiota are associated with increased symptom severity. The gut microbiota plays a pivotal role in modulating the gut–brain axis, potentially influencing neurodevelopmental processes and behavioral outcomes relevant to ASD (50). Recent studies also indicate that gut microbial composition can affect both cognitive and behavioral functions (51). Disruptions in the microbiota–gut–brain axis, especially microbial imbalances, are linked to neurobehavioral abnormalities and gastrointestinal dysfunction in ASD (52, 53).

The gut–brain axis refers to the bidirectional communication network between the gut and the brain, primarily mediated by the vagus nerve (54). Through this pathway, the vagus nerve interacts with the gut microbiota within the enteric nervous system (ENS), transmitting critical signals to the CNS, which processes the input and initiates appropriate responses (55). Studies have shown that the gut microbiota influences the gut–brain axis via neuroendocrine and metabolic pathways. It also directly interacts with the ENS, supporting the structural and functional development of the nervous system (56). These mechanisms affect brain function and may contribute to the development and progression of ASD (57).

Exercise can increase gut microbiota diversity, enrich beneficial bacteria such as butyrate-producing species, and modulate signaling along the microbiota–gut–brain axis. Concurrently, it elevates the expression of 5-HT, BDNF, and GABA, thereby regulating neurotransmitter balance, improving central nervous system function, enhancing neuronal antioxidant capacity and functionality, and ultimately contributing to the amelioration of cognitive performance, motor abilities, and stereotyped behaviors in individuals with ASD (18, 20). Recent studies have shown that an 8-week program of moderate-intensity aerobic exercise, performed 3–5 times per week for 40 minutes per session, can increase gut microbiota diversity, enrich beneficial bacteria, and reduce the expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. This intervention also attenuates excessive microglial activation and modulates signaling along the microbiota–gut–brain axis, thereby improving central nervous system function. Additionally, exercise enhances the activity of antioxidant enzymes such as SOD and GSH-Px, decreases ROS levels, elevates 5-HT and BDNF expression, and strengthens neuronal antioxidant capacity and functionality (20). Moreover, an 8-week program of combined exercise (aerobic plus resistance) or aerobic exercise, performed at least twice per week for 30–60 minutes per session at moderate intensity (60–75% Heart Rate/VO₂max), can optimize gut microbiota composition, enrich beneficial butyrate-producing bacteria such as Faecalibacterium prausnitzii and Roseburia hominis, and increase microbial diversity. This intervention also elevates GABA levels and regulates neurotransmitter balance, thereby exerting positive effects on cognitive function, motor performance, and stereotyped behaviors in individuals with ASD (18). (Figure 4) Studies of the gut microbiome have found that athletes exhibit greater microbial diversity compared to nonathletes. This effect is likely attributed to the enhanced metabolic flexibility induced by regular physical activity. Exercise-derived metabolites can act as energy sources or nutrients for specific microbial taxa. They may also exert physiological effects that shape microbial composition and promote microbial diversity in the gut. The study indicates that moderate-intensity aerobic exercise (60–75% Heart Rate/VO₂max), performed three times per week for 8–12 weeks, is relatively effective (58, 59).