The advancement of neuroimaging methods has significantly increased the ability to observe alterations in the morphology and brain activation patterns of individuals diagnosed with ASD over the past decades. In particular, since the late 1980s, when the first research of ASD using magnetic resonance imaging (MRI) was published, various MRI modalities, including different types of functional MRI, structural MRI, and diffusion tensor imaging, have been reported to effectively facilitate the non-invasive clinical diagnosis of ASD. These publications emphasize that the clinical symptoms of ASD are correlated with volumetric abnormalities in different areas of the brain, including the hippocampus. For instance, extensive MRI research has demonstrated abnormalities in hippocampal volume in individuals with ASD when compared to typically developing people, which is proven to be associated with aberrant autobiographical memory, impaired language skills, social communication deficit, and emotional problems in individuals with ASD (32–34).

Sussman and co-workers (35) have observed a decreased relative volume of the left hippocampus in 72 children and adolescents with ASD. Similarly, a study comparing autistic adults without intellectual disability and healthy community volunteers, found that the reduction in hippocampal volume in the autistic subjects was apparent when corrected for total brain volume (36). Another research based on the ABIDE database also found decreased gray-matter volume in the posterior hippocampus among a large sample of participants with ASD as compared to typically developing controls (32). As these studies all included high-functioning autistic individuals (Full-Scale IQ > 80), the reduction in hippocampal volume is likely to reflect features of autism itself, rather than features of the intellectual deficits that typically accompany autism (36). In other words, autistic traits have a robust correspondence with reduced brain volume in the hippocampus that is related to social processing, working memory, perceptual reasoning, and spatial learning. One possible hypothesis is that high-functioning autistic populations may experience an adaptive reduction in hippocampal volume as a result of their decreased specific functional demands on the hippocampus and altered interactions with the environment (37). Decreased hippocampal volume in ASD individuals was also related to impaired language skills, including verbal learning and memory (32, 38). It has also been suggested that left hippocampal volume is a positive predictor of early language development in females, but not in males (39). Furthermore, it is worth mentioning that in many studies that have reported reductions in hippocampal volume among ASD subjects, only reductions in relative hippocampal volume (percentage of total brain volume) have been observed rather than the absolute volume (35, 36, 40). Numerous studies have now firmly established that individuals with ASD have a significantly larger head circumference and a higher prevalence of macrocephaly than age-matched healthy subjects (41), which could explain the reduced relative hippocampal volume in the ASD group.

Surprisingly, in contrast to the aforementioned findings, an MRI study discovered larger volumes of the hippocampus bilaterally in ASD adults with IQ > 100 when compared to healthy controls (42). Likewise, Xu et al. (43) found evidence of larger absolute hippocampal volume in adults with ASD and adequate intelligence than that of healthy adults based on the ABIDE datasets. The Intense World Theory posits that ASD traits may be attributed to the activation of a molecular syndrome, which sensitizes gene expression pathways to excessively respond to environmental stimulation. Under normal circumstances, these pathways facilitate brain development through enriched environments; however, when sensitized, they can lead to accelerated brain development in response to environmental stimuli (44). This theory focuses on the neocortex and the amygdala, but it may also apply to other brain regions, such as the hippocampus. For example, the chronic stress process in ASD enhances amygdala activity, which may initially result in hypertrophy of the hippocampus as it moderates the amygdala activity through multiple reciprocal connections (34). The amygdala and hippocampus also play a major role in olfaction. Research has shown that the severity of taste and smell dysfunction is inversely related to the hippocampal volume, and females with ASD have more severe taste and olfactory impairment than males (45). These theories reflect characteristic behavioral variations in ASD and remain to be elucidated in the future. Another possible hypothesis suggests that the increased size of the hippocampus in people with ASD may be due to an enhancement in experience-dependent function (43, 46). Indeed, individuals with ASD have been reported to excel in certain cognitive domains for which the hippocampus is responsible (e.g. visuospatial abilities) compared to typically developing individuals, but these differences may be driven by task demands (31). Current scientific opinion still holds that ASD can lead to a range of hippocampus-related dysfunctions, which are linked to abnormalities in the volume of the hippocampus (32–34). The assertion that individuals with ASD are more proficient than their neurotypical peers in a specific hippocampus-dependent function is a limited occurrence and cannot be generalized to the entire autistic population (4).

In addition to these observations, a number of researches have reported no difference in the hippocampal volume between ASD individuals and healthy volunteers (47–49). The above inconsistent findings on hippocampal size can actually be attributed to the heterogeneity of ASD individuals. For example, the age range is a significant confounding factor because individuals with ASD appear to consistently have larger hippocampus than their healthy peers from childhood to adolescence (46), but in adulthood, their hippocampus begins to decrease (36), or in some cases, remain stable (47). Although several studies have reported no correlation between age and hippocampal volume in individuals with ASD (35, 42), this may be because of the broad age range of participants, which appears to neutralize the disparities. Second, sex is another important determinant of hippocampal volume in people with ASD. Possibly due to the higher prevalence of ASD in males, existing studies have included a larger sample of male participants. It has been reported that male ASD subjects had faster hippocampal volume growth and greater hippocampal asymmetry than female subjects (50, 51). Relative volumes of both the left and right hippocampus were smaller in females with ASD than in age-matched males (35, 39). Third, many studies have included autism, Asperger’s syndrome, and pervasive developmental disorder (32, 46–48), and a mixed population with varying levels of intellectual disabilities (33, 46, 48) and seizure disorders (52). There are also significant variations in medication statuses, brain MRI scanners, measurement approaches, controls for total brain volume, and anatomical definitions of the hippocampus in related studies. Furthermore, hippocampal abnormalities in ASD could potentially be genetically based, as evidenced by the larger hippocampal volume observed in parents of children with ASD compared to control subjects (53). Due to the high variability in hippocampal volume in typical individuals (54), and the current prevalence of cross-sectional studies with limited sample sizes, considerably more MRI studies will need to be done to determine hippocampal volume changes in ASD, particularly for a specific autistic group with large sample sizes and a longitudinal design.

Postmortem examinations were conducted in ten cases of ASD, comprising eight males and two females, with eight individuals presenting intellectual disability and five individuals exhibiting seizure disorder, ranging from 4 to 29 years old. The findings revealed reduced neural size and increased neuronal density within the hippocampal formation (55–57), similar to typical hippocampal developmental trends. It has previously been observed in an immunohistochemical study, that the density of parvalbumin-, calbindin-, and calretinin-immunoreactive interneurons within the subfields of the hippocampus was increased in cases of ASD compared to controls (58). Increased gray matter density was found in the hippocampal formation and peri-hippocampal cortex of children with ASD, correlating with symptoms of impaired social interaction and mnemonic function in ASD (59, 60). These observations of heightened neuron density in the hippocampal formation could be attributed to incorrect neuronal migration (59). The distorted shape of the dentate granule layer, forming irregular circles and loops, was indicative of abnormal neuronal migration and seemed to be another evidence of the phenomenon described above (61). Additionally, Golgi studies of CA4 and CA1 neurons revealed a noticeable decrease in dendritic branching complexity in two ASD children compared to their age-matched controls. Nevertheless, it remains uncertain whether increased hippocampal neuron density, fewer neuron size volumes, and dendritic branching lead to corresponding reductions in the macroscopic size of the hippocampus. If this is the case, it could account for the decrease in MRI volumes observed in the hippocampus of individuals with ASD. The dentate gyrus development distortion in ASD was manifested by granule cell migration to the molecular layer and the formation of an extra granule cell layer (61). A previous MRI evidence of ASD also suggested that significantly smaller cross-sectional areas of the area dentata than healthy subjects could be attributed to the hypoplasia of the dentate gyrus and CA4 subfield (52). However, caution should be exercised when interpreting these findings as this MRI study and prior neuroanatomical researches have included ASD individuals with seizure disorders that are known to be connected with a decrease in hippocampal volume (62). Moreover, most current autopsy studies have been conducted in males, and it is unclear whether there are sex differences in hippocampal pathological anatomy in ASD. Three-dimensional MRI measurements of hippocampal shape variation in children with ASD indicated an upward curvature in the head and tail of the hippocampus, as well as inward deformation in its medial aspect (48). In terms of morphological structure, the hippocampal regions in children with ASD may be the initial site of alteration and a significant area in brain imaging that can be utilized for diagnosing ASD in children (63). Considering that clinical autistic symptoms were associated with various structural abnormalities in hippocampal regions, additional neuropathological and imaging studies will be needed to obtain the objective criteria for early diagnosis of children with ASD based on the morphological changes of the hippocampus.

As documented through quantitative MRI and 3D pseudo-continuous arterial spin labeling, cerebral hypoperfusion has been observed in the hippocampus among children with ASD in comparison to healthy controls, which may not be related to sex differences (63–65). Proper brain oxygenation is essential not only for the early development of neurons but also for optimal functioning. Previous research has indicated a positive correlation between hippocampal blood flow and spatial memory performance (66). Therefore, measuring hippocampal blood flow may be an effective method for brain imaging diagnosis in children with ASD. The reduction in cerebral blood flow in the hippocampus also led to a decrease in hemoglobin iron and non-hemoglobin iron in the blood, which ultimately resulted in a decrease in iron content in the hippocampus (63, 65). The hippocampal growth is closely related to blood perfusion, but current findings suggest that reduced blood perfusion and iron ion levels within the hippocampal region do not have a significant impact on the hippocampal volume of ASD children (63–65). One contradictory result was that as compared to healthy controls, high-functioning ASD adults showed a significant cerebral blood flow increase in the right parahippocampal cortex (67). Differences in functional ability and sedative use among the included ASD participants may explain this inconsistency.

Previous magnetic resonance spectroscopy studies have suggested altered chemical metabolism in hippocampal regions in ASD. Most studies of the hippocampus have reported a trend toward reduced N-acetylaspartate concentrations and N-acetylaspartate/creatine ratios in children with ASD (21, 68, 69). N-acetyl-aspartate synthesis occurs exclusively in the mitochondria of neuronal cells and is widely accepted as a marker for axonal and neuronal integrity and viability (70), so a diminished level of N-acetyl-aspartate may signify an irregularity in hippocampal regional neuronal development and mitochondrial function. This hypothesis was corroborated by a previous study that demonstrated a positive correlation between N-acetyl-aspartate levels in the right hippocampal region and performance IQ in the ASD group (69). However, among adult subjects, Page et al. (71) and O’Brien et al. (72) discovered no variation in NAA levels between the ASD group and the matched comparison group. The impact of age on alterations to metabolites in distinct areas of the brain has been evidenced; for instance, NAA levels are diminished in a neonate and subsequently surge during cerebral development (70). When comparing only boys with and without ASD, there were also no differences in NAA, choline, and creatine concentrations in the hippocampal region (73). People with ASD had a significantly higher concentration of glutamate+glutamine, aka Glx in the amygdala-hippocampal complex than comparison subjects (71), which is consistent with prior data in the auditory cortex of people with ASD (74). As glutamate is the most abundant excitatory neurotransmitter, the pathogenesis of ASD is likely to be associated with increased hippocampal excitability. Previous researches have identified an association between choline/creatine ratio elevation within the hippocampus and the severity of autistic symptoms, including language impairment (69, 75). Similarly, high concentrations of creatine and phosphocreatine in the hippocampal formation of ASD individuals had a significant positive correlation with their aggressive behaviors (70, 76). In sum, it can be hypothesized that disturbances of metabolic substances in the hippocampus are associated with abnormalities in hippocampus-dependent functions.

In the study of the autistic human hippocampus, functional MRI has emerged as a powerful tool for mapping disrupted functional connectivity, which denotes the measurement of the temporal synchronization of activity between the hippocampus and other brain regions while a person is at rest or involved in a given cognitive activity. For example, in ASD children and adolescents, the resting-state functional connectivity strength between the left posterior hippocampus and the posterior cingulate cortex has a significant negative correlation with successful memory performance (77). Aberrant circuitry between the hippocampus and posterior cingulate cortex was found to be a common feature in ASD associated with reduced general and facial memory (78). A preliminary neuropsychological and neuroanatomical investigation has indicated that hippocampal and parahippocampal abnormalities are associated with memory deficits in low-functioning ASD individuals, which in turn undermines their learning and language abilities (20). Earlier data from experimental tasks suggested that adults with ASD had particular difficulties with structural learning due to changes in the function of the hippocampus, which played a critical role in the aetiology of ASD (19). During learning, strong functional connectivity was observed between the hippocampus and caudate in both ASD and typically developing adolescents, but this connectivity was positively associated with task performance in ASD and negatively associated with performance in typically developing adolescents (79). Infants with low familial risk for developing ASD exhibited stronger resting-state functional connectivity between the right posterior superior temporal gyrus and the right hippocampus, as well as parahippocampal gyrus, in comparison to high-risk infants. The atypical and immature functional connectivity in high-risk infants could cascade into their later language deficits (80). During the emotional resonance condition, boys with ASD displayed reduced responses in the bilateral hippocampus, indicating potential difficulties with emotional information integration (81). Neural abnormalities within the hippocampus area may potentially place young individuals with ASD at risk for anxiety or other emotional and behavioral dysfunctions (82). Finally, in spatial memory tasks involving the dorsolateral prefrontal-hippocampal circuit, people with ASD showed worse performance than typical controls (83). When performing the virtual reality shopping task, participants with ASD also displayed lower activation in the parahippocampal gyrus, which is implicated in scene recognition and spatial navigation (84). These studies investigate a range of functional domains linked to the hippocampus, indicating that altered functional connectivity between the hippocampal region and other brain networks may account for diverse autism symptoms.

As discussed above, changes in hippocampal volume, morphology, blood flow, metabolites, and functional connectivity may underlie altered hippocampal functions, including the formation and consolidation of memory, learning, language abilities, emotional regulation, and cognitive map creation ( Figure 2 ).

It is widely accepted that ASD is a heritable disorder with origins in copy number variants, unusual mutations of a single gene, and cumulative effects of particular gene variants (85). To date, hundreds of genetically modified models (especially monogenic models) have intentionally replicated identified human autistic syndromes, both syndromic and non-syndromic ASD. The genetic cause has been clearly defined in cases of syndromic ASD, which often presents alongside ASD-related behavioral phenotypes, and on the contrary, non-syndromic ASD lacks a distinct phenotype (86).

It is clear now ASD etiology involves both genetic and environmental factors or their possible combinations. Exposure of animals to given chemicals, toxins, viruses, and other agents during gestation can induce models of ASD in their offspring.

As genetic and environment-induced models cannot accurately replicate all the pathological features of ASD, strains of mice and rats have been developed using idiopathic models, which display robust and well-replicated behavioral characteristics of ASD such as social deficits and repetitive behaviors. The BTBR T+Itpr3tf/J (BTBR) strain is one of the most valid models of idiopathic ASD, and inbred strain C57BL/6J is often used as a control for BTBR (239).

Oxytocin has been proposed as a possible therapeutic agent for ASD due to its potent regulation of mammalian social behavior. The injection of oxytocin into the left lateral ventricle specifically improved the long-term social recognition memory and LTP at hippocampal synapses in Shank3-deficient rats (147). In vivo, subcutaneous oxytocin injections induced upregulation of hippocampal postsynaptic proteins PSD95 and Nlgn3 of Shank3 deficient mice (251). In rats exposed to VPA prenatally, chronic intranasal oxytocin administration rescued ASD-like behaviors including learning and memory impairments (198), and enhanced the expression of multiple genes in the hippocampus linked to synaptic function, learning, memory, and neurodevelopment (252). Erythropoietin, a glycoprotein hormone, has recently been reported to inhibit the astrogliosis in the hippocampal CA1 subfield in both LPS (227) and VPA (266) induced rat models of ASD, contributing to the enhanced learning and memory task performance (227). A preliminary study in VPA-treated rats has shown that melatonin treatment restored hippocampal CaMKII/PKA/PKC phosphorylation and LTP reduction, which might correlate with amelioration of hippocampus-dependent memory and learning skills (253).

Recent RNA sequencing research has found that vitamin A supplementation significantly alleviated VPA-induced anxiety behaviors, possibly by regulating lncRNA-mRNA co-expression networks (particularly lncRNA NONRATT021475.2 and Desert hedgehog gene) in the hippocampus of ASD rats (254). Gestational B-vitamin supplementation (vitamin B6, folic acid, and vitamin B12) has the potential to mitigate PM2.5-induced spatial learning and memory defects in mice offspring by ameliorating hippocampal inflammation, oxidative stress, mitochondrial damage, neuronal apoptosis, and synaptic dysfunction (236). Likewise, using solely folic acid rescued hippocampal neuron death and spatial learning and memory impairments in BTBR mice as it suppressed oxidative stress, inflammation, and ferroptosis in the hippocampus (240). Regarding mineral supplementation, selenium has a protective effect on the hippocampus of BTBR mice, with a comparable mechanism to that of folic acid (241). A six-week zinc water supplementation led to a decrease in anxiety-like behavior and seizure susceptibility in BTBR mice. This effect may be related to the restoration of neural progenitor cell proliferation and excitation/inhibition balance in the hippocampus (250). Lithium treatment can rescue olfactory-based learning and memory defects in drosophila fragile X model, and increase the cAMP signaling by inhibiting GSK-3β activity in the hippocampus of fragile X mice (255). In addition, lithium exerts an anti-inflammatory role probably by reducing microglial activation and inflammatory cytokine release and increasing levels of H3K9 acetylation in the hippocampus of VPA-exposed rats, with beneficial implications for improving social memory and anxiety levels (211).

The third-generation, atypical antipsychotic drugs aripiprazole, and risperidone are the only medications approved by the American FDA for ASD treatment. Data from several studies suggest that chronic treatments with aripiprazole attenuated VPA-induced visual recognition memory (207) and spatial learning and memory (201) impairments in mouse/rat offspring with ASD. More importantly, maternal treatment with aripiprazole prevents working memory deficits and hippocampal cell death in juvenile mice exposed to VPA during the prenatal period (210). Chronic administrations of risperidone improved VPA-induced memory impairment and reductions in hippocampal dendritic spine density, but there was no improvement with acute administrations (207). In addition, risperidone impeded hippocampal glutamate excitotoxicity in the VPA rat model of ASD, ultimately promoting neuronal survival (219). Similarly, the antipsychotic olanzapine can alleviate VPA-induced impairments in recognition and spatial memory by mitigating neuroplastic alterations in the hippocampus, including neuronal hypotrophy, reduced spine density, and elongated dendritic length (203).

The phosphodiesterase class of enzymes is responsible for the degradation of cAMP, which affects various neurobiological processes from neuroinflammation to learning and memory formation (267). For instance, ibudilast, a phosphodiesterase-4 inhibitor, was found to elevate levels of oxidative stress markers (SOD, GSH, CAT) and lower levels of pro-inflammatory markers (IL-1β, TNF-α, IL-6) in the hippocampus of VPA exposed rats. Meanwhile, these ASD rats administered with two doses of ibudilast showed significantly reduced deficits in learning/memory and anxious behaviors (199). In the same way, Luhach and colleagues have demonstrated that vinpocetine, cilostazol, and papaverine, all of which are phosphodiesterase inhibitors, positively influenced neurogenesis, neuronal survival, synaptic transmission, neuronal transcription, neuronal inflammation, and neuronal oxidative stress in the hippocampus of VPA-exposed rat models (213–215). Both rolipram (phosphodiesterase-4 inhibitor) and BAY-60-7550 (phosphodiesterase-2 inhibitor) treatment abrogated the exaggerated hippocampal mGluR-LTD observed in fragile X mice, which can be attributed to significantly increased cAMP levels (88, 255, 268). In like manner, rolipram treatment rescued the LTP of hippocampal CA1 neurons to a significant level in Rett syndrome mice (269). Lastly, rolipram rescued olfactory-based long-term memory defects of drosophila fragile X models (255, 268).

Sertraline and fluoxetine function as primary selective serotonin reuptake inhibitors, impeding 5-hydroxytryptamine uptake into presynaptic vesicles from the synaptic cleft in the central nervous system. Chronic treatment with sertraline improved autistic-like features in Cdkl5 KO mice, including hippocampus-dependent spatial learning and memory deficiency. This positive behavioral effect was associated with restored neuronal survival, dendritic development, and synaptic connectivity in the dentate gyrus and CA1 pyramidal neurons (256). Recent evidence suggests that fluoxetine can ameliorate social behavior in Nlgn3-KO mice, at least in part, by promoting adult hippocampal neurogenesis (257). More typically, long-term fluoxetine treatment normalizes hippocampal parvalbumin-positive interneurons number and glucocorticoid signaling of Angelman syndrome model mice, which is important for the restoration of anxiety-like behaviors (129). On the contrary, however, Fmr1 KO mice after fluoxetine treatment have reduced anxiety but enhanced explorative activity during the open field test, with abnormal changes of BDNF/TrkB signaling in the hippocampus (105). Activation with selective serotonin reuptake inhibitors has been observed in people with fragile X syndrome, which can manifest as mood changes and disinhibited behavior (270). What calls for special attention is the subsequent risk of ASD with exposure to selective serotonin reuptake inhibitors during pregnancy. Recent findings underscored that maternal fluoxetine exposure impaired hippocampal LTP, spatial discrimination, and spatial learning in adult offspring (271), accompanied by decreased hippocampal neurogenesis and hippocampal IL-10, IFN-γ and IL-13 levels (272).

Dysregulation of mTOR signaling is strongly associated with ASD, and the inhibition of mTOR can prevent the binding of mTOR with other protein components and reduce mTOR phosphorylation (273). For example, rapamycin, as a prominent mTOR inhibitor, has been shown to effectively block the hippocampal mTORC1 signaling of Pten mutant mice (258). Besides, rapamycin plays a crucial role in promoting autophagy (220) and decreasing apoptosis (220, 221) in the hippocampus of VPA-induced neonatal rats of ASD, thereby improving learning and memory ability (221). As discussed earlier, tuberous sclerosis complex models had increased hippocampal neuron volume, blood flow, and oxygen consumption. Correspondingly, the administration of rapamycin has been reported to lower cerebral blood flow and oxygen consumption in hippocampal regions of the Tsc2 mutant rat, potentially by downregulating Akt signals (146). This also accords with previous observations, which showed that pharmacological inhibition of mTORC suppressed granule cell hypertrophy in Pten mutant mice (258) and inhibited the PI3K/AKT/mTOR signaling pathway in VPA-induced rats (220).

Bumetanide, a loop diuretic that inhibits the Na-K-Cl cotransporter, has been reported to improve core symptoms of ASD in children over recent years (274). In VPA-treated rats, even a brief maternal bumetanide treatment can prevent hippocampal overgrowth in their offspring (275). In addition, maternal pretreatment with bumetanide effectively restored elevated hippocampal intracellular chloride levels, increased hippocampal excitatory GABA, and enhanced hippocampal gamma oscillations in offspring of VPA-induced rats and Fmr1 mutant mice (259). Recently, a new selective Na-K-Cl cotransporter inhibitor called ARN23746 has been reported to improve sociability in VPA-induced mice, similar to bumetanide (276). The oral administration of torasemide, a diuretic that also acts as a Na-K-Cl cotransporter inhibitor, has the potential to enhance neuronal viability and reduce astrogliosis in the hippocampus of ASD rat models (277).

The dysregulated signaling mediated via mGluR5 contributes to the pathophysiology of ASD since it acts as a crucial regulator of excitatory and inhibitory signaling in the hippocampus (278). After treatment with the mGluR5 antagonist MPEP, epileptiform activity and ERK signaling in the hippocampal slices of Tsc2 mutant mice can be suppressed. The blocked mGluR-LTD in the CA3 hippocampus via antagonism of mGluR5 also improved reversal learning performance between these mice (142). Similarly, for the BTBR mouse model, MPEP treatment facilitated hippocampus-dependent object location memory and decreased synaptic p-ERK1/2 levels (242). Like lithium and rolipram, fragile X syndrome flies treated with mGluR5 antagonist LY341495 demonstrated an enhanced long-term memory paradigm compared to controls (255). Long-term antagonism of mGluR5 also rescued immature spine phenotype (89) and decreased GSK-3β activity (255) in the hippocampus of Fmr1-KO mice.

NMDAR-mediated excitation and inhibition imbalance is one of the primary theories explaining the neurotoxicity in ASD. Data from several studies on rats exposed to VPA indicate that the NMDAR antagonist, agmatine (260) and dextromethorphan (200), normalize the overly active ERK1/2 phosphorylation in the hippocampus, which serves as an indicative marker of hippocampal hyperexcitability state. Besides, spatial memory and learning deficits induced by Fmr1-KO and VPA were mitigated following agmatine (100) and dextromethorphan (200) administration, respectively. For both rats exposed to VPA and those with a Mecp2-KO, the administration of ketamine produces a positive effect on their autistic-like behaviors by improving synaptic molecule levels in the dentate gyrus of the hippocampus (222). Memantine, a non-competitive antagonist of NMDAR, was reported to alleviate anxiety and improve learning and memory deficits in VPA-exposed rats, which could be mediated via the restoration of hippocampal GABA/glutamate balance and inhibition of hippocampal neurofibrillary tangles formation and neuronal apoptosis (201).

The histamine H3R, as a presynaptic autoreceptor can regulate the production and release of histamine as well as numerous brain neurotransmitters like dopamine and acetylcholine (279). Thus, selective H3R antagonists can improve the cognitive impairment in ASD. It is evident from the observation that the administration of histamine H3R antagonists ST-2223 (247) and ST-713 (248) significantly elevated the levels of histamine, dopamine, and acetylcholine in the hippocampal tissue of BTBR mice with anxiolytic-like effects. Administration of ciproxifan could improve the VPA-induced LTP decline in the CA1 area and hippocampus-dependent learning and memory capacity (202). Moreover, the histamine H3R antagonist E100 mitigates VPA-induced hippocampal inflammation by reducing the levels of IL-6, IL-1β, TNF-α, and TGF-β and by suppressing the expression of NF-κB, iNOS, and COX-2 (216).

The insulin-like growth factor (IGF) system comprising two activating ligands (IGF-1 and IGF-2) greatly impacts the development of the central nervous system. It has been discovered that levels of IGF-1 are reduced in the hippocampus of Rett syndrome mouse model (280). The active peptide derivative of IGF-1 can cross the blood-brain barrier and rescue Rett syndrome symptoms in MeCP2 mutant mice (281). In addition, daily intraperitoneal injections of IGF-1 for 2 weeks reversed deficits in hippocampal LTP in Shank3-deficient mice (282). Previous data revealed that Nlgn3 KO mice treated with IGF-2 fully recovered the social novelty discrimination. This effect was not accompanied by any alteration in spontaneous glutamatergic synaptic transmission within the CA2 region, but rather by enhanced CA2 neuronal excitability (283). Similarly, the administration of IGF-2 ameliorated social interaction deficits in BTBR mice and enhanced their social novelty memory via hippocampal IGF-2 receptor (261). In the Angelman syndrome mouse model, the impaired contextual and recognition memories as well as working memory deficits were restored following subcutaneous injection of IGF-2 (284).

The beneficial effects on memory functions of aerobic exercise, as a non-pharmacological intervention, have been well-documented in individuals with ASD (285). Compared to sedentary controls, both Cdkl5 KO mice (262) and VPA-induced rats (204) after one month of wheel/treadmill running showed increased hippocampal neurogenesis, improved memory performance, and reduced anxious and impulsive behaviors. One-month voluntary wheel running not only can decrease hippocampal microglia overactivation in Cdkl5 KO mice (262), but also stimulate microglia-mediated engulfment of surplus synapses in the granule cell axons observed in MIA mice (229). On the other hand, however, high-intensity exercise may produce negative effects on ASD symptoms. For instance, two-month treadmill training with relatively high speed led to impaired social memory in ASD rats with mercury exposure (286). Voluntary running for seven days increased cell proliferation in the hippocampal dentate gyrus of Fmr1 KO mice, but this effect was not observed when running for 28 days (263). Swimming is another beneficial aerobic exercise that has been shown to increase hippocampal gray matter volume and dendritic spine density in Shank3-KO rats (152) and to prevent hippocampal neuroinflammation in VPA-exposed mice (208). It also contributes to improvements in spatial, working, social, and visual recognition memory (152, 208).

Environmental enrichment is a novel living condition with increased social exploration opportunities and sensory, cognitive, and motor stimulations, which positively affect the hippocampus-dependent learning, memory, and anxiety behavior of children with ASD (287). Living with the mother and an additional non-lactating female (enhanced maternal stimulation) can rescue the spatial and contextual fear memory deficits displayed in adulthood by Fmr1-KO mice (90). In addition to this “social environmental enrichment”, enrichment in housing conditions (running wheel, toys, tunnels, ladders, etc.) also ameliorates impaired anxiety-like behavior (91, 209, 264), visual recognition memory (209, 264), spatial learning and memory (91, 265), and fear memory (91), potentially by acting on the hippocampal BDNF/TrkB-PLCγ1-CaMKII pathway (91, 209, 264, 265), as observed in Fmr1-KO mice (91), VPA-exposed mice (209), Ube3a-KO mice (264), and MIA rats (265).