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NMDAR autoantibodies from the seropositive healthy subject (Healthy+) and the seropositive ASD patient (ASD+) do not differ in their capacity to alter synaptic NMDAR dynamics. (A) Schematic representation of the experimental design. Before tracking GluN2A-NMDAR-QD complexes, hippocampal cultures (13 to 15 days in vitro) were incubated for 30 minutes with different purified type G immunoglobulin (IgG) samples from a seropositive healthy subject from the cohort (Healthy+), a seropositive ASD patient from the cohort (ASD+), or three pooled healthy seronegative subjects (Healthy-). (B) Representative trajectories of GluN2A-NMDAR-QD complexes (500 frames, 50 ms acquisition) at the plasma membrane in the presence of NMDAR-Ab from Healthy+ and ASD+. Synapses (in green) are identified with Mitotracker. Scale bar: 500 nm. (C) Synaptic mean square displacement (MSD) of GluN2A-NMDAR-QD complexes in the absence (Healthy-) or presence (Healthy+, ASD+) of NMDAR-Ab. (D) Cumulative frequency of the synaptic GluN2A-NMDAR-QD complexes diffusion coefficient in the absence (Healthy-) or presence (Healthy+, ASD+) of NMDAR-Ab. (E) Comparison of GluN2A-NMDAR diffusion coefficient in the absence (Healthy-) or presence (Healthy+, ASD+) of NMDAR-Ab at glutamate synapses (median diffusion coefficient ± 25%-75% IQR, Healthy-= 0.107 µm 2 /s, IQR= 0.034-0.197 µm 2 /s, n= 492; Healthy+ = 0.089 µm 2 /s, interquartile range (IQR) = 0.036-0.185 µm 2 /s, n= 490; ASD+ = 0.102 µm 2 /s, IQR= 0.039-0.186 µm 2 /s, n= 555; P = 0.81 Kruskal-Wallis test). Anti-GluN2A, anti-N-methyl-d-aspartate receptor 2A; ASD, autism spectrum disorder; ASD+, seropositive autism spectrum disorder patient; Cumul. freq., cumulative frequency; Diff. coeff., diffusion coefficient; Healthy+, seropositive healthy subject; Healthy-, seronegative healthy subject; IgG, type G immunoglobulin; QD, quantum dot; MSD, mean square displacement; NMDAR, N-methyl-d-aspartate receptor; NMDAR-Ab, N-methyl-d-aspartate receptor autoantibody.
Source publication
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by dysfunctions in social interactions resulting from a complex interplay between immunogenetic and environmental risk factors. Autoimmunity has been proposed as a major etiological component of ASD. Whether specific autoantibodies directed against brain targets are invol...
Contexts in source publication
Context 1
... dot (QD) tracking of the endogenous GluN2A-NMDAR subunit was per- formed on live hippocampal neurons at day 13 to day 15 in vitro. Neurons were first incubated (30 min) with purified IgG (5 µg/mL) from either the seropositive ASD patient (ASD+), the seropositive healthy subject (healthy+), or seronegative healthy subjects (healthy-) ( Figure 1A). QD labeling and microscopy were per- ASD, autism spectrum disorder; ASD+, seropositive autism spectrum disorder patient; Cumul. ...
Context 2
... then explored the possibility that the circulat- ing NMDAR-Ab from this patient, and not from the healthy+ subject, altered NMDAR trafficking and sig- naling, 12 possibly contributing to the symptomatology. 15 For this, NMDAR-Ab IgGs were purified from the ASD patient and the seropositive healthy subject, and both IgGs were used to perform single-nanoparticle tracking on surface NMDAR in live hippocampal neurons (Fig- ure 1A). Incubation for at least 30 minutes with purified IgGs from either the ASD patient or the seropositive healthy subject did not alter the surface trafficking of GluN2A-NMDAR when compared with seronegative healthy subjects ( Figure 1B-E). ...
Context 3
... For this, NMDAR-Ab IgGs were purified from the ASD patient and the seropositive healthy subject, and both IgGs were used to perform single-nanoparticle tracking on surface NMDAR in live hippocampal neurons (Fig- ure 1A). Incubation for at least 30 minutes with purified IgGs from either the ASD patient or the seropositive healthy subject did not alter the surface trafficking of GluN2A-NMDAR when compared with seronegative healthy subjects ( Figure 1B-E). This was assessed by measuring the MSD curves and instantaneous diffusion coefficients of surface GluN2A-NMDAR ( Figure 1B- E). ...
Context 4
... for at least 30 minutes with purified IgGs from either the ASD patient or the seropositive healthy subject did not alter the surface trafficking of GluN2A-NMDAR when compared with seronegative healthy subjects ( Figure 1B-E). This was assessed by measuring the MSD curves and instantaneous diffusion coefficients of surface GluN2A-NMDAR ( Figure 1B- E). Together, these data indicate that the NMDAR-Ab purified from the ASD patient or from a seropositive healthy subject do not alter the surface trafficking of NMDAR and thus probably have no effect on NM- DAR signaling. ...
Citations
... However, the anti-NMDAR antibodies in patients with schizophrenia and anti-NMDAR encephalitis did not compete for binding to live cultured neurons, and mutation of the N368 region could only partially interfere anti-NMDAR antibody binding [26,28]. Moreover, anti-NMDAR antibodies from healthy controls or patients with autism spectrum disorder did not affect surface NMDAR expression [26,29]. These results highly suggested the presence of other epitopes outside the N368/G369 region and intrinsic differences in activity or affinity among anti-NMDAR antibodies. ...
Background
The development of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis following viral encephalitis, such as Japanese encephalitis, has received increasing attention in recent years. However, the mechanism of anti-NMDAR antibody production following Japanese encephalitis has not been explored.
Methods
A peptide from the Japanese encephalitis virus (JEV), which shares a similar amino acid sequence with GluN1, was identified by sequence comparison. We then explored whether active subcutaneous immunization with the JEV peptide could induce the production of anti-NMDAR antibodies and related pathophysiological and behavioral changes in mice. In addition, a published active immune model of anti-NMDAR encephalitis using a GluN1 peptide was used as the positive control.
Results
A 6-amino-acid sequence with 83 % similarity between the envelope protein of the JEV (HGTVVI) and GluN1 (NGTHVI) was identified, and the sequence included the N368/G369 region. Active immunization with the JEV peptide induced a substantial and specific immune response in mice. However, anti-NMDAR antibodies were not detected in the serum of mice immunized with the JEV peptide by ELISA, CBA, and TBA. Moreover, mice immunized with the JEV peptide presented no abnormities related to anti-NMDAR antibodies according to western blotting, patch clamp, and a series of behavioral tests. In addition, active immunization with a recently reported GluN1 peptide failed to induce anti-NMDAR antibody production in mice.
Conclusions
In this study, the attempt of active immunization with the JEV peptide to induce the production of anti-NMDAR antibodies via molecular mimicry failed. The pathogenesis of anti-NMDAR encephalitis following Japanese encephalitis remains to be elucidated.
... In addition to an encephalitis characterized by an array of neuropsychiatric signs and symptoms that can be mistaken for psychosis and catatonia, elevated titers of anti-NMDA receptor antibodies in serum and CSF have been associated with impaired sociability (e.g., lack of empathy and difficulty apprehending intentions of others) [59][60][61]. For example, a normally developing 9-year-old boy was described with a history of good social and academic performance, whose initial presentation was an acute onset of secondary generalized seizures that progressed to an agitated catatonia with posturing and dyskinetic movements, and followed by a "robotic state" with mutism, negativism, and marked social withdrawal [59]. ...
... Although this is speculative, NMDA receptor hypofunction or disturbed function may confer a lower reserve of functional NMDA receptor mediated neurotransmission capability and, thus, greater vulnerability to deleterious consequences of NMDA receptor autoantibodies. Importantly, elevated levels of anti-NMDA-receptor antibodies are found in seemingly unaffected persons [61]. ...
... Of interest, type G immunoglobulin purified from a 53-year-old normally intelligent male with autism did not disrupt the translational movement of assembled NMDA receptors within the membranes of dissociated hippocampal neurons prepared from E18 Sprague Dawley rats [61]. The 53-year-old patient was shown to be seropositive for NMDA receptor autoantibodies using a cell-based assay that detected their binding to HEK293 cells transfected with the GluN1 and GluN2B-NMDA receptor subunits. ...
Various ASD risk alleles have been associated with impairment of NMDA receptor activation (i.e., NMDA Receptor Hypofunction) and/or disturbance of the careful balance between activation mediated by GluN2B-subtype and GluN2A-subtype-containing NMDA receptors. Importantly, although these various risk alleles affect NMDA receptor activation through different mechanisms, they share the pathogenic consequences of causing disturbance of highly regulated NMDA receptor activation. Disturbances of NMDA receptor activation due to sequence variants, protein termination variants and copy number variants are often cell-specific and regionally selective. Thus, translational therapeutic NMDA receptor agonist interventions, which may require chronic administration, must have specificity, selectivity and facilitate NMDA receptor activation in a manner that is physiologic (i.e., mimicking that of endogenously released glutamate and glycine/D-serine released in response to salient and relevant socio-cognitive provocations within discrete neural circuits). Importantly, knockout mice with absent expression and mice with haploinsufficient expression of the deleterious genes often serve as good models to test the potential efficacy of promising pharmacotherapeutic strategies. The Review considers diverse examples of “illness” genes, their pathogenic effects on NMDA receptor activation and, when available, results of studies of impaired sociability in mouse models, including “proof of principle/proof of concept” experiments exploring NMDA receptor agonist interventions and the development of promising positive allosteric modulators (PAMs), which serve as support and models for developing an inventory of PAMs and negative allosteric modulators (NAMs) for translational therapeutic intervention. Conceivably, selective PAMs and NAMs either alone or in combination will be administered to patients guided by their genotype in order to potentiate and/or restore disrupted balance between activation mediated by GluN2B-subtype and GluN2A-subtype containing NMDA receptors.
... NMDAR-Abs from healthy individuals lack most of the molecular pathogenicity reported in anti-NMDAR encephalitis, NPLSE or any other NMDARautoimmune disorder (Jezequel et al., 2018). In addition, NMDAR-Abs from an autism spectrum disorder patient also failed to alter NMDAR synaptic trafficking (Grea et al., 2017). Still, the diversity of NMDAR-Ab pathogenicity goes even further. ...
Over the past decades, the identification of autoimmune encephalitis in which patients express autoantibodies directed against neurotransmitter receptors has generated great hope to shed new light on the molecular mechanisms underpinning neurological and psychiatric conditions. Among these autoimmune encephalitides, the discovery of autoantibodies directed against the glutamatergic NMDA receptor (NMDAR-Ab), in the anti-NMDAR encephalitis, has provided some key information on how complex neuropsychiatric symptoms can be caused by a deficit in NMDAR signalling. Yet, NMDAR-Abs have also been detected in several neurological and psychiatric conditions, as well as in healthy individuals. In addition, these various NMDAR-Abs appear to have different molecular properties and pathogenicities onto receptors and synaptic functions. Here, we discuss the current view on the variety of NMDAR-Abs and, in particular, how these autoantibodies can lead to receptor dysfunction in neuronal networks. Since our mechanistic understanding on patients' NMDAR-Abs is still in its infancy, several complementary processes can be proposed and further in-depth molecular and cellular investigations will surely reveal key insights. Autoantibodies represent a great opportunity to gain knowledge on the etiology of neuropsychiatric disorders and pave the way for innovative therapeutic strategies.
One sentence summary
Current view on patients' autoantibody against NMDAR.
... For instance, a systemic pro-inflammatory profile including circulating antibodies targeting lymphocyte antigens was identified in serum of mothers with ASD children (Edmiston et al. 2018), which positively correlates with an increase in the susceptibility to ASD after birth (Chen et al. 2016). In fact, serum autoantibodies against fetal neuronal migration and neural network brain targets, including the collapsin response mediator proteins 1 and 2 (CRMP1 and CRMP2), cypin, and the Y-box binding protein 1 and the N-methyl-D-aspartate receptor for glutamatergic neurotransmission, have been identified in mothers of ASD people (Edmiston et al. 2018;Fox-Edmiston and Van de Water 2015;Brimberg et al. 2013;Gréa et al. 2017). Notably, in a recent exploratory study, Krakowiak P. et al (2017) reported that metabolic failure related to gestational diabetes was associated with an up to 3.2- ...
Autism spectrum disorder (ASD) is a complex neurodevelopmental disease which involves functional and structural defects in selective central nervous system (CNS) regions that harm function and individual ability to process and respond to external stimuli. Individuals with ASD spend less time engaging in social interaction compared to non‐affected subjects. Studies employing structural and functional magnetic resonance imaging reported morphological and functional abnormalities in the connectivity of the mesocorticolimbic reward pathway between the nucleus accumbens and the ventral tegmental area (VTA) in response to social stimuli, as well as diminished medial prefrontal cortex in response to visual cues, whereas stronger reward system responses for the non‐social realm (e.g., video games) than social rewards (e.g., approval), associated with caudate nucleus responsiveness in ASD children. Defects in the mesocorticolimbic reward pathway have been modulated in transgenic murine models using D2 dopamine receptor heterozygous (D2+/−) or dopamine transporter knockout mice, which exhibit sociability deficits and repetitive behaviors observed in ASD phenotypes. Notably, the mesocorticolimbic reward pathway is modulated by systemic and central inflammation, such as primed microglia, which occurs during obesity or maternal overnutrition. Therefore, we propose that a positive energy balance during obesity/maternal overnutrition coordinates a systemic and central inflammatory crosstalk that modulates the dopaminergic neurotransmission in selective brain areas of the mesocorticolimbic reward pathway. Here, we will describe how obesity/maternal overnutrition may prime microglia, causing abnormalities in dopamine neurotransmission of the mesocorticolimbic reward pathway, postulating a possible immune role in the development of ASD.
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... Regarding the autoantibody against GAD65, we could not confirm the significance reported by Rout et al. [11]. Recently, there have been reports of an association between ASD and anti-glutamate NMDA receptor antibodies [35,36]. The etiology of ASD is multi-factorial [37]. ...
Objective
Mental health is an essential issue during adolescence. The number of students who use counseling services is increasing in universities. We attempted to confirm the characteristics of the students who access counseling services using both psychological tests and pulse rate variability (PRV) for better support for students’ academic success.
Methods
We recruited the participants for this study from the students who had counseling sessions at Kanazawa University (Group S). As a control group, we also recruited students who had no experience in counseling services (Group H). We obtained health information from the database of annual health checkups. Participants received the Wechsler Adult Intelligence Scale (WAIS)-III, Autism-Spectrum Quotient (AQ), Sukemune-Hiew (S-H) Resilience Test, and State-Trait Anxiety Inventory-JYZ (STAI). We also studied the 12-Item Short-Form Health Survey (SF-12v2) for testing Health-Related Quality of Life (HRQOL). As a physiological test, we examined the spectral analyses of pulse rate variability (PRV) by accelerating plethysmography. We performed a linear analysis of PRV for low-frequency power (LF: 0.02–0.15 Hz) and high-frequency power (HF: 0.15–0.50 Hz). We also conducted a non-linear analysis of PRV for the largest Lyapunov exponent (LLE). Additionally, we examined participants’ blood for autoantibodies against glutamate decarboxylase (GAD) 65.
Results
A total of 105 students participated in this study. Group S had 37 participants (Male: 26, Female: 11), and Group H had 68 participants (Male: 27, Female 41). There were five males and one female in Group S who had diagnoses of autism spectrum disorder (ASD), and three males in Group S were diagnosed with attention deficit hyperactivity disorder (ADHD) by medical institutes. Additionally, four males and two females in Group S had diagnoses of ASD with ADHD by medical institutes. A male with ASD in Group S had epilepsy. The students of Group S had characteristics as follows: 1) lower power of Working Memory Index (WMI) despite high Full-Scale Intelligent Quotient (FSIQ), 2) higher ASD traits especially in Male, 3) lower resilience powers, 4) higher anxiety trait, 5) lower Health-Related Quality of Life (HRQOL) in Role/social component in both Male and Female, 6) lower HRQOL in Mental component in Male 7) shifting of autonomic nervous balance toward higher sympathetic activity.
Conclusion
We could confirm the characteristics of students who visited counseling rooms for mental support (Group S). We also found gender differences in specificities of Group S. The educational system is changing rapidly to adjust social requests. These changes make conflict with the features of students of Group S. We should think about appropriate supports for the students who would pioneer the future of humanity.
... Heterozygotes of both sexes exhibited a significantly reduced acoustic startle response (B6NJ, Fig. 4C; F 1 , data not shown) despite mice of both genotypes having auditory brainstem response thresholds of 20 dB sound pressure level, indicating that hearing was not impaired per se but that the response to stimulus was altered. Because NMDAR mutations are associated with autism spectrum disorder (Hacohen et al., 2016;Grea et al., 2017;Rossi et al., 2017) and repetitive behaviour in mice (Lee et al., 2015;Kim et al., 2019), we evaluated repetitive behaviours using established criteria for rodents (see 'Materials and methods' section). S644G/ + heterozygotes of both sexes and strain backgrounds exhibited a significant increase in repetitive behaviours, which included vertical jumping, backflips and self-grooming (Fig. 4D). ...
NMDA receptors play crucial roles in excitatory synaptic transmission. Rare variants in GRIN2A encoding the GluN2A subunit are associated with a spectrum of disorders, ranging from mild speech and language delay to intractable neurodevelopmental disorders, including but not limited to developmental and epileptic encephalopathy. A de novo missense variant, p.Ser644Gly, was identified in a child with this disorder, and Grin2a knock-in mice were generated to model and extend understanding of this intractable childhood disease. Homozygous and heterozygous mutant mice exhibited altered hippocampal morphology at 2 weeks of age, and all homozygotes exhibited lethal tonic-clonic seizures by mid-third week. Heterozygous adults displayed susceptibility to induced generalized seizures, hyperactivity, repetitive and reduced anxiety behaviours, plus several unexpected features, including significant resistance to electrically-induced limbic seizures and to pentylenetetrazole induced tonic-clonic seizures. Multielectrode recordings of neuronal networks revealed hyperexcitability and altered bursting and synchronicity. In heterologous cells, mutant receptors had enhanced NMDA receptor agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. NMDA receptor-mediated synaptic currents in heterozygous hippocampal slices also showed a prolonged deactivation time course. Standard antiepileptic drug monotherapy was ineffective in the patient. Introduction of NMDA receptor antagonists was correlated with a decrease in seizure burden. Chronic treatment of homozygous mouse pups with NMDA receptor antagonists significantly delayed the onset of lethal seizures but did not prevent them. These studies illustrate the power of using multiple experimental modalities to model and test therapies for severe neurodevelopmental disorders, while revealing significant biological complexities associated with GRIN2A developmental and epileptic encephalopathy.
... Importantly, NMDAR-Ab from different origins (patients versus healthy carriers) do not necessarily share the same molecular impact on the glutamatergic and dopaminergic receptor trafficking. This is consistent with previous finding demonstrating that NMDAR-Ab from healthy carriers or patient with autism spectrum disorder without history of psychosis do not alter NMDAR surface trafficking (12,25). Our data further highlight that NMDAR-Ab are diverse in their mechanisms of action and call for further investigations to decrypt the alterations on the targeted NMDAR and its membrane partners. ...
Circulating autoantibodies directed against extracellular domains of the glutamatergic N-methyl-D-aspartate receptors (NMDAR-Ab) elicit psychotic symptoms in humans and behavioral deficits in animal models. Recent advances suggest that NMDAR-Ab exert their pathogenic action by altering the trafficking of NMDAR, which results in a synaptic NMDAR hypofunction consistent with the consensual glutamatergic hypothesis of psychotic disorders. Yet, dysfunction in the dopaminergic signaling is also proposed to be at the core of psychotic disorders. Since NMDAR and dopamine D1 receptors (D1R) form membrane signaling complexes, we investigated whether NMDAR-Ab purified from patients with NMDAR-encephalitis or schizophrenia impaired D1R surface dynamics. As previous data demonstrated that NMDAR-Ab, at least from NMDAR-encephalitis patients, mainly bind to hippocampal NMDAR, we used single nanoparticle imaging to track D1R specifically at the surface of hippocampal neurons that were exposed to either purified G type immunoglobulins (IgGs) from NMDAR-Ab seropositive patients suffering from NMDAR-encephalitis or schizophrenia, or control IgGs from healthy NMDAR-Ab seropositive or seronegative subjects. We report that overnight incubation with NMDAR-Ab from patients, but not from healthy carriers, decreased the surface dynamics of D1R compared with NMDAR-Ab seronegative IgGs. This decrease was abolished, and even reversed, in D1R mutant that cannot physically interact with NMDAR. Overall, our data indicate that NMDAR-Ab from patients with psychotic symptoms alter the trafficking of D1R, likely through the surface crosstalk between NMDAR and D1R.
... Heterozygotes of both sexes exhibited a significantly reduced acoustic startle response ( Fig. 4c; Supplementary Fig. 6) but a normal auditory brainstem response threshold (Fig. 4c inset), indicating that hearing per se was not impaired but the reaction to stimulus is altered. Because NMDAR mutations are associated with autism spectrum disorder (ASD, (Hacohen et al., 2016;Grea et al., 2017;Rossi et al., 2017) and repetitive behavior in mice (Lee et al., 2015;Kim et al., 2019), we evaluated additional ASD-relevant behaviors using established criteria in rodents. Although S644G/+ mice showed no impairments in the same-sex reciprocal social interaction test (Supplementary Fig. 7a-b), both sexes and strain backgrounds exhibited a significant increase in repetitive behaviors, such as vertical jumping and self-grooming (Fig. 4d-e; Supplementary Fig. 7c-d). ...
NMDA receptors (NMDAR) play crucial roles in excitatory synaptic transmission. Rare variants of GRIN2A, which encodes the GluN2A NMDAR subunit, are associated with several intractable neurodevelopmental disorders, including developmental and epileptic encephalopathy (DEE). A de novo missense variant, p.Ser644Gly (c.1930A>G), was identified in a child with DEE, and Grin2a knockin mice were generated to model and extend understanding of this intractable childhood disease. Homozygous and heterozygous mutant mice exhibit altered hippocampal morphology at two weeks of age, and homozygotes exhibit lethal tonic-clonic seizures in the third week. Heterozygous adult mice display a variety of distinct features, including resistance to electrically induced partial seizures, as well as hyperactivity and repetitive and reduced anxiety behaviors. Multielectrode recordings of mutant neuronal networks reveal hyperexcitability and altered bursting and synchronicity. When expressed in heterologous cells, mutant receptors exhibit enhanced NMDAR agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. Consistent with these observations, NMDAR-mediated synaptic currents in hippocampal slices from mutant mice show a prolonged deactivation time course. Standard antiepileptic drug monotherapy was ineffective in the patient, but combined treatment of NMDAR antagonists with antiepileptic drugs substantially reduced the seizure burden albeit without appreciable developmental improvement. Chronic treatment of homozygous mutant mouse pups with NMDAR antagonists delayed the onset of lethal seizures but did not prevent them. These studies illustrate the power of modeling severe neurodevelopmental seizure disorders using multiple experimental modalities and suggest their extended utility in identifying and evaluating new therapies.
... Regarding the autoantibody against GAD65, we could not confirm the significance 307 reported by Rout et al. [12] Recently, there have been reports of an association between 308 ASD and anti-glutamate NMDA receptor antibodies [28,29]. The etiology of ASD is 309 thought to be multi-factorial. ...
Objective
The number of students who use counseling services is increasing in universities. We clarified the characteristics of the students who access counseling services using both psychological tests and pulse rate variability (PRV).
Methods
We recruited the participants for this study from the students who had counseling sessions at Kanazawa University (Group S). As a control group, we also recruited students who had no experience in counseling sessions (Group H). We obtained health information from the database of annual health check-ups. Participants received the Wechsler Adult Intelligence Scale (WAIS) III, Autism-Spectrum Quotient (AQ), Sukemune-Hiew (S-H) Resilience Test, and State-Trait Anxiety Inventory-JYZ (STAI). We also studied the SF-12v2 Health Survey. We examined the spectral analyses of pulse rate variability (PRV) by accelerating plethysmography. We performed linear analysis of PRV for LF, HF, and LF/HF as indexes of autonomic nervous function. We also performed non-linear analysis of PRV for the largest Lyapunov exponent (LLE). We examined participants' blood for autoantibodies against glutamate decarboxylase (GAD) 65.
Results
A total of 105 students participated in this study. Group S had 37 participants (Male: 26, Female: 11) and Group H had 68 participants (Male: 27, Female 41). There were 12 males and two females who had been diagnosed with autism spectrum disorder (ASD) in Group S. Group S had 1) lower Working Memory Index (WMI) despite relatively high Full-Scale IQ, 2) higher AQ scores, 3) lower resilience scores, 4) higher anxiety scores, 5) lower QOL in social health, and 6) shifting of autonomic nervous balance toward higher sympathetic activity. There were only two participants who had the anti-GAD65 antibody in Group S, and one participant had the anti-GAD65 antibody in Group H.
Conclusion
The results of our study revealed valuable information about the students who seek mental support in our university. Our results provide information that can be used in interventions for the university students who need counseling services.
... In fact, serum autoantibodies against fetal neuronal migration and neural network brain targets, including the lactate dehydrogenase A and B (LDH-A and LDH-B), the stress-induced phosphoprotein 1 (STIP1), the collapsin response mediator proteins 1 and 2 (CRMP1 and CRMP2), cypin, and the Y-box binding protein 1 (YBX1), have been identified in ASD subjects (Edmiston et al., 2017;Fox-edmiston et al., 2016). Of note, serum autoantibodies in ASD subjects have also been identified against brain targets, such as the N-methyl-D-aspartate (NMDA) receptor for glutamatergic neurotransmission (Gréa et al., 2017). Finally, immunogenetic analysis confirm the hypothesis of autoimmunity as a etiological cause of ASD by identifying a third hypervariable region (HVR-3) and the C4 complement alleles have been correlated to ASD (Gesundheit et al., 2013). ...
Autism spectrum disorder (ASD) is a complex neurodevelopmental disease which involves functional and structural defects in selective central nervous system (CNS) regions harming capability to process and respond to external stimuli. In addition to genetic background, etiological causes of ASD have not been fully clarified. Maternal immune activation (MIA) during pregnancy have been proposed as a potential etiological cause leading to aberrant synaptic pruning and microglia-mediated neurogenesis impairment. Several clinical studies suggest that pro-inflammatory profile during maternal obesity associates with a higher risk of having a child with autism. In this context, the effect of maternal programing by high fat diet overconsumption during pregnancy sets a pro-inflammatory profile partly dependent on an epigenetic program of immunity which promotes brain micro and macrostructural abnormalities in the offspring that might last through adulthood accompanied by phenotypic changes in ASD subjects. Of note, maternal programming of inflammation during development seems to integrate the CNS and peripheral immune system cross-talk which arrays central inflammatory domains coordinating ASD behavior. In this review, we discuss basic and clinical studies regarding the effects of obesity-induced MIA on peripheral immune cells and microglia priming and their relationship with brain structural alterations in ASD models. Also, we show supportive evidence stating the role of maternal programming on epigenetic gene activation in immune cells of ASD subjects. We suggest that maternal programming by hypercaloric diets during development sets a central and peripheral immune cross-talk which potentially might modulate brain macro and microstructural defects leading to autism susceptibility.
