RESUMEN

A large body of evidence implies the involvement of brain-derived neurotrophic factor (BDNF) in the pathogenesis of autism spectrum disorders (ASDs). A deficiency of BDNF in the hippocampus and frontal cortex of BTBR mice (a model of autism) has been noted in a number of studies. Earlier, we showed that induction of BDNF overexpression in the hippocampus of BTBR mice reduced anxiety and severity of stereotyped behavior, but did not affect social interest. Here, we induced BDNF overexpression in the frontal cortex neurons of BTBR mice using an adeno-associated viral vector, which resulted in a significant increase in the social interest in the three-chamber social test. At the same time, the stereotypy, exploratory behavior, anxiety-like behavior, and novel object recognition were not affected. Therefore, we have shown for the first time that the presence of BDNF in the frontal cortex is critical for the expression of social interest in BTBR mice, since compensation for its deficiency in this structure eliminated the autism-like deficiencies in the social behavior characteristic for these animals.

Asunto(s)

Trastorno Autístico , Factor Neurotrófico Derivado del Encéfalo , Modelos Animales de Enfermedad , Lóbulo Frontal , Conducta Social , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Lóbulo Frontal/metabolismo , Ratones , Trastorno Autístico/metabolismo , Trastorno Autístico/genética , Masculino , Conducta Animal , Ratones Endogámicos C57BL

RESUMEN

Currently, there are no reliable biomarkers for autism diagnosis. The heterogeneity of autism and several co-occurring conditions are key challenges to establishing these. Here, we used untargeted mass spectrometry-based urine metabolomics to investigate metabolic differences for autism diagnosis and autistic traits in a well-characterized twin cohort (N = 105). We identified 208 metabolites in the urine samples of the twins. No clear, significant metabolic drivers for autism diagnosis were detected when controlling for other neurodevelopmental conditions. However, we identified nominally significant changes for several metabolites. For instance, phenylpyruvate (p = 0.019) and taurine (p = 0.032) were elevated in the autism group, while carnitine (p = 0.047) was reduced. We furthermore accounted for the shared factors, such as genetics within the twin pairs, and report additional metabolite differences. Based on the nominally significant metabolites for autism diagnosis, the arginine and proline metabolism pathway (p = 0.024) was enriched. We also investigated the association between quantitative autistic traits, as measured by the Social Responsiveness Scale 2nd Edition, and metabolite differences, identifying a greater number of nominally significant metabolites and pathways. A significant positive association between indole-3-acetate and autistic traits was observed within the twin pairs (adjusted p = 0.031). The utility of urine biomarkers in autism, therefore, remains unclear, with mixed findings from different study populations.

Asunto(s)

Trastorno Autístico , Biomarcadores , Metabolómica , Humanos , Trastorno Autístico/orina , Trastorno Autístico/metabolismo , Trastorno Autístico/genética , Masculino , Femenino , Metabolómica/métodos , Niño , Biomarcadores/orina , Adolescente , Metaboloma , Adulto , Gemelos Monocigóticos , Preescolar

RESUMEN

Members of the leucine rich repeat (LRR) and PDZ domain (LAP) protein family are essential for animal development and histogenesis. Densin-180, encoded by LRRC7, is the only LAP protein selectively expressed in neurons. Densin-180 is a postsynaptic scaffold at glutamatergic synapses, linking cytoskeletal elements with signalling proteins such as the α-subunit of Ca2+/calmodulin-dependent protein kinase II. We have previously observed an association between high impact variants in LRRC7 and Intellectual Disability; also three individual cases with variants in LRRC7 had been described. We identify here 33 individuals (one of them previously described) with a dominant neurodevelopmental disorder due to heterozygous missense or loss-of-function variants in LRRC7. The clinical spectrum involves intellectual disability, autism, ADHD, aggression and, in several cases, hyperphagia-associated obesity. A PDZ domain variant interferes with synaptic targeting of Densin-180 in primary cultured neurons. Using in vitro systems (two hybrid, BioID, coimmunoprecipitation of tagged proteins from 293T cells) we identified new candidate interaction partners for the LRR domain, including protein phosphatase 1 (PP1), and observed that variants in the LRR reduced binding to these proteins. We conclude that LRRC7 encodes a major determinant of intellectual development and behaviour.

Asunto(s)

Agresión , Trastorno Autístico , Discapacidad Intelectual , Humanos , Discapacidad Intelectual/genética , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Agresión/fisiología , Masculino , Femenino , Niño , Células HEK293 , Neuronas/metabolismo , Adolescente , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Adulto , Animales , Preescolar , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Adulto Joven , Sinapsis/metabolismo , Dominios PDZ/genética

RESUMEN

INTRODUCTION: Neuroinflammation and microglial activation-related dendritic injury contribute to the pathogenesis of Autism Spectrum Disorder (ASD). Previous studies show that Progranulin (PGRN) is a growth factor associated with inflammation and synaptic development, but the role of PGRN in autism and the mechanisms underlying changes in PGRN expression remain unclear. AIMS: To investigate the impact of PGRN in autism, we stereotactically injected recombinant PGRN into the hippocampus of ASD model rats. Additionally, we explored the possibility that sortilin may be the factor behind the alterations in PGRN by utilizing SORT1 knockdown. Ultimately, we aimed to identify potential targets for the treatment of autism. RESULTS: PGRN could alleviate inflammatory responses, protect neuronal dendritic spines, and ameliorate autism-like behaviors. Meanwhile, elevated expression of sortilin and decreased levels of PGRN were observed in both ASD patients and rats. Enhanced sortilin levels facilitated PGRN internalization into lysosomes. Notably, suppressing SORT1 expression amplified PGRN levels, lessened microglial activation, and mitigated inflammation, thereby alleviating autism-like behaviors. CONCLUSION: Collectively, our findings highlight elevated sortilin levels in ASD rat brains, exacerbating dendrite impairment by affecting PGRN expression. PGRN supplementation and SORT1 knockdown hold potential as therapeutic strategies for ASD.

Asunto(s)

Proteínas Adaptadoras del Transporte Vesicular , Trastorno Autístico , Progranulinas , Ácido Valproico , Animales , Femenino , Humanos , Masculino , Ratas , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/genética , Trastorno Autístico/metabolismo , Trastorno Autístico/inducido químicamente , Trastorno Autístico/tratamiento farmacológico , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/patología , Espinas Dendríticas/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Microglía/metabolismo , Microglía/efectos de los fármacos , Progranulinas/genética , Ratas Sprague-Dawley , Ácido Valproico/farmacología

RESUMEN

One of the main drivers of autism spectrum disorder is risk alleles within hundreds of genes, which may interact within shared but unknown protein complexes. Here we develop a scalable genome-editing-mediated approach to target 14 high-confidence autism risk genes within the mouse brain for proximity-based endogenous proteomics, achieving the identification of high-specificity spatial proteomes. The resulting native proximity proteomes are enriched for human genes dysregulated in the brain of autistic individuals, and reveal proximity interactions between proteins from high-confidence risk genes with those of lower-confidence that may provide new avenues to prioritize genetic risk. Importantly, the datasets are enriched for shared cellular functions and genetic interactions that may underlie the condition. We test this notion by spatial proteomics and CRISPR-based regulation of expression in two autism models, demonstrating functional interactions that modulate mechanisms of their dysregulation. Together, these results reveal native proteome networks in vivo relevant to autism, providing new inroads for understanding and manipulating the cellular drivers underpinning its etiology.

Asunto(s)

Trastorno del Espectro Autista , Trastorno Autístico , Encéfalo , Modelos Animales de Enfermedad , Proteoma , Proteómica , Animales , Proteoma/metabolismo , Ratones , Humanos , Encéfalo/metabolismo , Proteómica/métodos , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/genética , Fenotipo , Edición Génica , Masculino , Predisposición Genética a la Enfermedad , Ratones Endogámicos C57BL , Femenino , Sistemas CRISPR-Cas

RESUMEN

This study aimed to evaluate the potential benefits of acetyl-L-carnitine (ALCAR) in the context of valproate-induced autism. After prenatal exposure to valproate (VPA; 600 mg/kg, i.p.) on embryonic day 12.5, followed by ALCAR treatment (300 mg/kg on postnatal days 21-49, p.o.), assessment of oxidative stress, mitochondrial membrane potential (MMP), mitochondrial biogenesis, parvalbumin interneurons, and hippocampal volume was conducted. These assessments were carried out subsequent to the evaluation of autism-like behaviors. Hippocampal analysis of oxidative factors (reactive oxygen species and malondialdehyde) and antioxidants (superoxide dismutase, catalase, and glutathione) revealed a burden of oxidative stress in VPA rats. Additionally, mitochondrial biogenesis and MMP were elevated, while the number of parvalbumin interneurons decreased. These changes were accompanied by autism-like behaviors observed in the three-chamber maze, marble burring test, and Y-maze, as well as a learning deficit in the Barnes maze. In contrast, administrating ALCAR attenuated behavioral deficits, reduced oxidative stress, improved parvalbumin-positive neuronal population, and properly modified MMP and mitochondrial biogenesis. Collectively, our results indicate that oral administration of ALCAR ameliorates autism-like behaviors, partly through its targeting oxidative stress and mitochondrial biogenesis. This suggests that ALCAR may have potential benefits ASD managing.

Asunto(s)

Acetilcarnitina , Trastorno Autístico , Hipocampo , Mitocondrias , Estrés Oxidativo , Ácido Valproico , Animales , Ácido Valproico/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Acetilcarnitina/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Trastorno Autístico/inducido químicamente , Trastorno Autístico/tratamiento farmacológico , Trastorno Autístico/metabolismo , Femenino , Masculino , Embarazo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratas , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/metabolismo , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Conducta Animal/efectos de los fármacos

RESUMEN

Chromogranin A (CgA), a âˆ¼ 49 kDa acidic secretory protein, is ubiquitously distributed in endocrine and neuroendocrine cells and neurons. As a propeptide, CgA is proteolytically cleaved to generate several peptides of biological importance, including pancreastatin (PST: hCgA250-301), Vasostatin 1 (VS1: hCgA1-76), and catestatin (CST: CgA 352-372). VS1 represents the most conserved fragment of CgA. A 20 amino acid domain within VS1 (CgA 47-66) exhibits potent antimicrobial and anti-inflammatory activities. Autism is known to be associated with inflammation. Therefore, we seek to test the hypothesis that VS1 modulates autism behaviors by reducing inflammation in the hippocampus. Treatment of C57BL/6 (B6) and BTBR (a mouse model of idiopathic autism) mice with VS1 revealed the following: BTBR mice showed a significant decrease in chamber time in the presence of a stranger or a novel object. Treatment with VS1 significantly increased chamber time in both cases, underscoring a crucial role for VS1 in improving behavioral deficits in BTBR mice. In contrast to chamber time, sniffing time in BTBR mice in the presence of a stranger was less compared to B6 control mice. VS1 did not improve this latter parameter. Surprisingly, sniffing time in BTBR mice in the presence of a novel object was comparable with B6 mice. Proinflammatory cytokines such as IL-6 and IL-1b, as well as other inflammatory markers, were elevated in BTBR mice, which were dramatically reduced after supplementation with VS1. Interestingly, even Beclin-1/p62, pAKT/AKT, and p-p70-S6K/p70-S6K ratios were notably reduced by VS1. We conclude that VS1 plays a crucial role in restoring autistic spectrum disorders (ASD) plausibly by attenuating neuroinflammation.

Asunto(s)

Trastorno Autístico , Cromogranina A , Modelos Animales de Enfermedad , Hipocampo , Enfermedades Neuroinflamatorias , Fragmentos de Péptidos , Animales , Masculino , Ratones , Trastorno Autístico/tratamiento farmacológico , Trastorno Autístico/metabolismo , Cromogranina A/farmacología , Cromogranina A/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Fragmentos de Péptidos/farmacología

RESUMEN

Atypical sensory processing is common in autism, but how neural coding is disrupted in sensory cortex is unclear. We evaluate whisker touch coding in L2/3 of somatosensory cortex (S1) in Cntnap2-/- mice, which have reduced inhibition. This classically predicts excess pyramidal cell spiking, but this remains controversial, and other deficits may dominate. We find that c-fos expression is elevated in S1 of Cntnap2-/- mice under spontaneous activity conditions but is comparable to that of control mice after whisker stimulation, suggesting normal sensory-evoked spike rates. GCaMP8m imaging from L2/3 pyramidal cells shows no excess whisker responsiveness, but it does show multiple signs of degraded somatotopic coding. This includes broadened whisker-tuning curves, a blurred whisker map, and blunted whisker point representations. These disruptions are greater in noisy than in sparse sensory conditions. Tuning instability across days is also substantially elevated in Cntnap2-/-. Thus, Cntnap2-/- mice show no excess sensory-evoked activity, but a degraded and unstable tactile code in S1.

Asunto(s)

Trastorno Autístico , Modelos Animales de Enfermedad , Proteínas de la Membrana , Proteínas del Tejido Nervioso , Corteza Somatosensorial , Vibrisas , Animales , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Corteza Somatosensorial/metabolismo , Corteza Somatosensorial/fisiopatología , Ratones , Trastorno Autístico/fisiopatología , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Ratones Noqueados , Tacto/fisiología , Ratones Endogámicos C57BL , Células Piramidales/metabolismo , Masculino , Proteínas Proto-Oncogénicas c-fos/metabolismo

RESUMEN

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder caused by the interaction of multiple pathogenic factors. Epidemiological studies and animal experiments indicate that maternal immune activation (MIA) is closely related to the development of ASD in offspring. A large number of pro-inflammatory cytokines are transferred from the placenta to the fetal brain during MIA, which impedes fetal neurodevelopment and is accompanied by activation of immune cells and microglia. Programmed cell death protein 1 (PD-1) can be highly expressed on the surface of various activated immune cells, when combined with programmed cell death-ligand 1 (PD-L1), it can activate the PD-1/PD-L1 pathway and exert powerful immunosuppressive effects, suggesting that this immune checkpoint may have the potential to treat MIA-induced ASD. This study combined bioinformatics analysis and experimental validation to explore the efficacy of Fc-fused PD-L1 (PD-L1-Fc) in treating MIA-induced ASD. Bioinformatics analysis results showed that in human placental inflammation, IL-6 was upregulated, T cells proliferated significantly, and the PD-1/PD-L1 pathway was significantly enriched. The experimental results showed that intraperitoneal injection of poly(I:C) induced MIA in pregnant mice resulted in significant expression of IL-6 in their serum, placenta, and fetal brain. At the same time, the expression of PD-1 and PD-L1 in the placenta and fetal brain increased, CD4+ T cells in the spleen were significantly activated, and PD-1 expression increased. Their offspring mice exhibited typical ASD-like behaviors. In vitro experiments on primary microglia of offspring mice have confirmed that the expression of IL-6, PD-1, and PD-L1 is significantly increased, and PD-L1-Fc effectively reduced their expression levels. In the prefrontal cortex of MIA offspring mice, there was an increase in the expression of IL-6, PD-1, and PD-L1; activation of microglial cells, and colocalization with PD-1. Then we administered brain stereotaxic injections of PD-L1-Fc to MIA offspring mice and intraperitoneal injections to MIA pregnant mice. The results indicated that PD-L1-Fc effectively suppressed neuroinflammation in the frontal cortex of offspring mice and partially ameliorated ASD-like behaviors; MIA in pregnant mice was significantly alleviated, and the offspring mice they produced did not exhibit neuroinflammation or ASD-like behaviors. In summary, we have demonstrated the therapeutic ability of PD-L1-Fc for MIA-induced ASD, aiming to provide new strategies and insights for the treatment of ASD.

Asunto(s)

Trastorno del Espectro Autista , Antígeno B7-H1 , Placenta , Receptor de Muerte Celular Programada 1 , Animales , Femenino , Antígeno B7-H1/metabolismo , Embarazo , Receptor de Muerte Celular Programada 1/metabolismo , Ratones , Masculino , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/prevención & control , Humanos , Placenta/metabolismo , Modelos Animales de Enfermedad , Efectos Tardíos de la Exposición Prenatal/inmunología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Conducta Animal , Ratones Endogámicos C57BL , Trastorno Autístico/metabolismo , Trastorno Autístico/inmunología , Inflamación/metabolismo , Interleucina-6/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos

RESUMEN

Autism spectrum disorders (ASD) can be caused by environmental factors. These factors act early in the development of the nervous system and induce stereotyped repetitive behaviors and diminished social interactions, among other outcomes. Little is known about how these behaviors are produced. In pregnant women, delivery of valproic acid (VPA) (to control seizure activity or stabilize mood) or immune activation by a virus increases the incidence of ASD in offspring. We found that either VPA or Poly Inosine:Cytosine (which mimics a viral infection), administered at mouse embryonic day 12.5, induced a neurotransmitter switch from GABA to glutamate in PV- and CCK-expressing interneurons in the medial prefrontal cortex by postnatal day 10. The switch was present for only a brief period during early postnatal development, observed in male and female mice at postnatal day 21 and reversed in both males and females by postnatal day 30. At postnatal day 90, male mice exhibited stereotyped repetitive behaviors and diminished social interaction while female mice exhibited only stereotyped repetitive behavior. Transfecting GAD1 in PV- and CCK-expressing interneurons at postnatal day 10, to reintroduce GABA expression, overrode the switch and prevented expression of autistic-like behavior. These findings point to an important role of neurotransmitter switching in mediating the environmental causes of autism.

Asunto(s)

Ácido Valproico , Ácido gamma-Aminobutírico , Animales , Femenino , Ratones , Masculino , Embarazo , Ácido Valproico/toxicidad , Ácido gamma-Aminobutírico/metabolismo , Interneuronas/metabolismo , Animales Recién Nacidos , Conducta Animal , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/patología , Glutamato Descarboxilasa/metabolismo , Glutamato Descarboxilasa/genética , Trastorno Autístico/etiología , Trastorno Autístico/metabolismo , Ácido Glutámico/metabolismo , Neurotransmisores/metabolismo , Poli I-C , Corteza Prefrontal/metabolismo , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/etiología , Trastorno del Espectro Autista/patología , Colecistoquinina/metabolismo , Parvalbúminas/metabolismo , Ratones Endogámicos C57BL , Conducta Estereotipada/efectos de los fármacos

RESUMEN

Maternal malnutrition has been associated with neurodevelopmental deficits and long-term implications on the offspring's health and behavior. Here, we investigated the effects of maternal low-protein diet (LPD) or obesity-inducing maternal high-fat diet (HFD) on dyadic social interactions, group organization and autism-related behaviors in mice. We found that maternal HFD induced an autism-related behavioral phenotype in the male offspring, including a robust decrease in sociability, increased aggression, cognitive rigidity and repetitive behaviors. Maternal LPD led to a milder yet significant effect on autism-related symptoms, with no effects on olfactory-mediated social behavior. Under naturalistic conditions in a group setting, this manifested in altered behavioral repertoires, increased magnitude in dominance relations, and reduced interactions with novel social stimuli in the HFD male offspring, but not in the LPD offspring. Finally, we found HFD-induced transcriptomic changes in the olfactory bulbs of the male offspring. Together, our findings show that maternal malnutrition induces long-lasting effects on aggression and autism-related behaviors in male offspring, and potential impairments in brain regions processing chemosensory signals.

Asunto(s)

Trastorno Autístico , Conducta Animal , Dieta Alta en Grasa , Dieta con Restricción de Proteínas , Conducta Social , Animales , Dieta Alta en Grasa/efectos adversos , Femenino , Masculino , Ratones , Trastorno Autístico/etiología , Trastorno Autístico/metabolismo , Embarazo , Dieta con Restricción de Proteínas/efectos adversos , Agresión , Efectos Tardíos de la Exposición Prenatal/metabolismo , Ratones Endogámicos C57BL , Fenómenos Fisiologicos Nutricionales Maternos , Bulbo Olfatorio/metabolismo , Modelos Animales de Enfermedad , Obesidad/metabolismo , Obesidad/etiología

RESUMEN

BACKGROUND: The neurobiological underpinnings of Autism Spectrum Disorder (ASD) are diverse and likely multifactorial. One possible mechanism is increased oxidative stress leading to altered neurodevelopment and brain function. However, this hypothesis has mostly been tested in post-mortem studies. So far, available in vivo studies in autistic individuals have reported no differences in glutathione (GSH) levels in frontal, occipital, and subcortical regions. However, these studies were limited by the technically challenging quantification of GSH, the main brain antioxidant molecule. This study aimed to overcome previous studies' limitations by using a GSH-tailored spectroscopy sequence and optimised quantification methodology to provide clarity on GSH levels in autistic adults. METHODS: We used spectral editing proton-magnetic resonance spectroscopy (1H-MRS) combined with linear combination model fitting to quantify GSH in the dorsomedial prefrontal cortex (DMPFC) and medial occipital cortex (mOCC) of autistic and non-autistic adults (male and female). We compared GSH levels between groups. We also examined correlations between GSH and current autism symptoms, measured using the Autism Quotient (AQ). RESULTS: Data were available from 31 adult autistic participants (24 males, 7 females) and 40 non-autistic participants (21 males, 16 females); the largest sample to date. The GSH levels did not differ between groups in either region. No correlations with AQ were observed. CONCLUSION: GSH levels as measured using 1H-MRS are unaltered in the DMPFC and mOCC regions of autistic adults, suggesting that oxidative stress in these cortical regions is not a marked neurobiological signature of ASD.

Asunto(s)

Trastorno del Espectro Autista , Trastorno Autístico , Glutatión , Lóbulo Occipital , Humanos , Masculino , Femenino , Glutatión/metabolismo , Glutatión/análisis , Adulto , Lóbulo Occipital/metabolismo , Lóbulo Occipital/diagnóstico por imagen , Trastorno del Espectro Autista/metabolismo , Trastorno Autístico/metabolismo , Adulto Joven , Espectroscopía de Protones por Resonancia Magnética , Lóbulo Frontal/metabolismo , Estrés Oxidativo , Persona de Mediana Edad , Corteza Prefrontal/metabolismo , Corteza Prefrontal/diagnóstico por imagen

RESUMEN

The objective of this investigation was to examine the impact of multiple exposures to general anesthesia (GA) with sevoflurane on the offspring of pregnant mice, as well as to elucidate the underlying mechanism. Neurodevelopmental assessments, including various reflexes and behavioral tests, were conducted on the offspring in the GA group to evaluate neuronal cell development. Furthermore, neonatal mouse neuronal cells were isolated and transfected with a high-expression CREB vector (pcDNA3.1-CREB), followed by treatment with sevoflurane (0.72 mol/L), ZD7288 (50 µmol/L), and KN-62 (10 µmol/L), or a combination of these compounds. The expression of relevant genes was then analyzed using qRT-PCR and western blot techniques. In comparison to the sham group, neonatal mice in the GA group exhibited significantly prolonged latencies in surface righting reflex, geotaxis test, and air righting reflex. Furthermore, there was a notable deceleration in the development of body weight and tail in the GA group. These mice also displayed impairments in social ability, reduced reciprocal social interaction behaviors, diminished learning capacity, and heightened levels of anxious behaviors. Additionally, synaptic trigger malfunction was observed, along with decreased production of c-Fos and neurotrophic factors. Sevoflurane was found to notably decrease cellular c-Fos and neurotrophic factor production, as well as the expression of HCN2 and CaMKII/CREB-related proteins. The inhibitory effects of sevoflurane on HCN2 or CaMKII channels were similar to those observed with ZD7288 or KN-62 inhibition. However, overexpression of CREB mitigated the impact of sevoflurane on neuronal cells. Repetitive exposure to sevoflurane general anesthesia while pregnant suppresses the CaMKII/CREB pathway, leading to the development of autism-like characteristics in offspring mice through the reduction of HCN2 expression.

Asunto(s)

Anestésicos por Inhalación , Trastorno Autístico , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Regulación hacia Abajo , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Efectos Tardíos de la Exposición Prenatal , Sevoflurano , Animales , Sevoflurano/farmacología , Sevoflurano/toxicidad , Ratones , Embarazo , Femenino , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Anestésicos por Inhalación/farmacología , Anestésicos por Inhalación/toxicidad , Anestésicos por Inhalación/efectos adversos , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/metabolismo , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/genética , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Canales de Potasio/metabolismo , Canales de Potasio/genética , Células Cultivadas , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL

RESUMEN

Autism spectrum disorder (ASD) is a group of neurodevelopment disorders characterized by deficits in social interaction and communication, and repetitive or stereotyped behavior. Autistic children are more likely to have vision problems, and ASD is unusually common among blind people. However, the mechanisms behind the vision disorders in autism are unclear. Stabilizing WNT-targeted scaffold protein Axin2 by XAV939 during embryonic development causes overproduction of cortical neurons and leads to autistic-like behaviors in mice. In this study, we investigated the relationship between vision abnormality and autism using an XAV939-induced mouse model of autism. We found that the mice receiving XAV939 had decreased amplitude of bright light-adaptive ERG. The amplitudes and latency of flash visual evoked potential recorded from XAV939-treated mice were lower and longer, respectively than in the control mice, suggesting that XAV939 inhibits visual signal processing and conductance. Anatomically, the diameters of RGC axons were reduced when Axin2 was stabilized during the development, and the optic fibers had defective myelin sheaths and reduced oligodendrocytes. The results suggest that the WNT signaling pathway is crucial for optic nerve development. This study provides experimental evidence that conditions interfering with brain development may also lead to visual problems, which in turn might exaggerate the autistic features in humans.

Asunto(s)

Proteína Axina , Modelos Animales de Enfermedad , Potenciales Evocados Visuales , Nervio Óptico , Animales , Proteína Axina/metabolismo , Ratones , Potenciales Evocados Visuales/fisiología , Nervio Óptico/metabolismo , Nervio Óptico/patología , Electrorretinografía , Ratones Endogámicos C57BL , Axones/patología , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/metabolismo , Masculino , Vía de Señalización Wnt/fisiología , Trastorno del Espectro Autista/fisiopatología , Trastorno del Espectro Autista/metabolismo , Trastorno Autístico/fisiopatología , Trastorno Autístico/metabolismo

RESUMEN

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by repetitive behaviors and altered communication abilities. Exercise is a low-cost intervention that could improve cognitive function and improve brain plasticity mechanisms. Here, the valproic acid (VPA) model was utilized to induce ASD-like phenotypes in rodents. Animals were exercised on a treadmill and performance was evaluated on a cognitive flexibility task. Biomarkers related to exercise and plasticity regulation were quantified from the prefrontal cortex, hippocampus, and skeletal muscle. Exercised VPA animals had higher levels of hippocampal BDNF compared to sedentary VPA animals and upregulated antioxidant enzyme expression in skeletal muscle. Cognitive improvements were demonstrated in both sexes, but in different domains of cognitive flexibility. This research demonstrates the benefits of exercise and provides evidence that molecular responses to exercise occur in both the central nervous system and in the periphery. These results suggest that improving regulation of BDNF via exercise, even at low intensity, could provide better synaptic regulation and cognitive benefits for individuals with ASD.

Asunto(s)

Factor Neurotrófico Derivado del Encéfalo , Cognición , Modelos Animales de Enfermedad , Hipocampo , Condicionamiento Físico Animal , Ácido Valproico , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Animales , Hipocampo/metabolismo , Masculino , Condicionamiento Físico Animal/fisiología , Femenino , Cognición/fisiología , Ácido Valproico/farmacología , Ratas , Trastorno del Espectro Autista/metabolismo , Músculo Esquelético/metabolismo , Corteza Prefrontal/metabolismo , Trastorno Autístico/metabolismo

RESUMEN

Alterations in steroid hormone regulation have been implicated in the etiology and progression of autism spectrum disorders (ASD), with the enzyme cytochrome P450 family 11 subfamily A member 1 (CYP11A1)-a key catalyst in cholesterol side-chain cleavage, prominently expressed in the adrenal glands, ovaries, testes, and placenta-standing at the forefront of these investigations. The potential link between aberrations in placental Cyp11a1 expression and the resultant neurodevelopmental disorders, along with the mechanisms underpinning such associations, remains inadequately delineated. In this study, we employed a placental trophoblast-specific Cyp11a1 Hipp11 (H11) knock-in murine model to dissect the phenotypic manifestations within the placenta and progeny, thereby elucidating the underlying mechanistic pathways. Behavioral analyses revealed a diminution in social interaction capabilities alongside an augmented anxiety phenotype, as evidenced by open field and elevated plus maze assessments; both phenotypes were ameliorated after vitamin D3 supplementation. Electrophysiological assays underscored the augmented inhibition of paired-pulse facilitation, indicating impaired neuroplasticity in Cyp11a1 H11-modified mice. An elevation in progesterone concentrations was noted, alongside a significant upregulation of Th1-related cytokines (IL-6 and TNFα) across the plasma, placental, and frontal cortex-a pathological state mitigable through vitamin D3 intervention. Western blotting revealed a vitamin D-mediated rectification of vitamin D receptor and PGC-1α expression dysregulations. Immunofluorescence assays revealed microglial activation in the knock-in model, which was reversible upon vitamin D3 treatment. In conclusion, Cyp11a1 overexpression in the placenta recapitulated an autism-like phenotype in murine models, and vitamin D3 administration effectively ameliorated the resultant neurobehavioral and neuroinflammatory derangements. This study substantiates the application of Cyp11a1 as a biomarker in prenatal diagnostics and posits that prenatal vitamin D3 supplementation is a viable prophylactic measure against perturbations in steroid hormone metabolism associated with ASD pathogenesis.

Asunto(s)

Trastorno del Espectro Autista , Encéfalo , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol , Modelos Animales de Enfermedad , Placenta , Animales , Femenino , Embarazo , Placenta/metabolismo , Ratones , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/metabolismo , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/genética , Encéfalo/metabolismo , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/genética , Vitamina D/metabolismo , Masculino , Trastorno Autístico/metabolismo , Trastorno Autístico/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Progesterona/metabolismo , Técnicas de Sustitución del Gen

RESUMEN

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is marked by impaired social interactions, and increased repetitive behaviors. There is evidence of genetic changes in ASD, and several of these altered genes are linked to the process of DNA repair. Therefore, individuals with ASD must have improved DNA repair efficiency to mitigate risks associated with ASD. Despite numerous milestones in ASD research, the disease remains incurable, with a high occurrence rate and substantial financial burdens. This motivates scientists to search for new drugs to manage the disease. Disruption of glucagon-like peptide-1 (GLP-1) signaling, a regulator in neuronal development and maintains homeostasis, has been associated with the pathogenesis and progression of several neurological disorders, such as ASD. Our study aimed to assess the impact of semaglutide, a new GLP-1 analog antidiabetic medication, on behavioral phenotypes and DNA repair efficiency in the BTBR autistic mouse model. Furthermore, we elucidated the underlying mechanism(s) responsible for the ameliorative effects of semaglutide against behavioral problems and DNA repair deficiency in BTBR mice. The current results demonstrate that repeated treatment with semaglutide efficiently decreased autism-like behaviors in BTBR mice without affecting motor performance. Semaglutide also mitigated spontaneous DNA damage and enhanced DNA repair efficiency in the BTBR mice as determined by comet assay. Moreover, administering semaglutide recovered oxidant-antioxidant balance in BTBR mice. Semaglutide restored the disrupted DNA damage/repair pathways in the BTBR mice by reducing Gadd45a expression and increasing Ogg1 and Xrcc1 expression at both the mRNA and protein levels. This suggests that semaglutide holds great potential as a novel therapeutic candidate for treating ASD traits.

Asunto(s)

Reparación del ADN , Péptidos Similares al Glucagón , Animales , Masculino , Péptidos Similares al Glucagón/farmacología , Reparación del ADN/efectos de los fármacos , Ratones , Modelos Animales de Enfermedad , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Expresión Génica/efectos de los fármacos , Hipoglucemiantes/farmacología , Trastorno Autístico/tratamiento farmacológico , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Conducta Animal/efectos de los fármacos

RESUMEN

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by alterations and imbalances in multiple brain neurochemical systems, particularly the serotonergic neurotransmission. This includes changes in serotonin (5-HT) levels, aberrations in 5-HT transporter activity, and decreased synthesis and expression of 5-HT receptors (5-HT7Rs). The exact role of the brain 5-HT system in the development of ASD remains unclear, with conflicting evidence on its involvement. Recently, we have reported research has shown a significant decrease in serotonergic neurons originating from the raphe nuclei and projecting to the CA1 region of the dorsal hippocampus in autistic-like rats. Additionally, we have shown that chronic activation of 5-HT7Rs reverses the effects of autism induction on synaptic plasticity. However, the functional significance of 5-HT7Rs at the cellular level is still not fully understood. This study presents new evidence indicating an upregulation of 5-HT7R in the CA1 subregion of the hippocampus following the induction of autism. The present account also demonstrates that activation of 5-HT7R with its agonist LP-211 can reverse electrophysiological abnormalities in hippocampal pyramidal neurons in a rat model of autism induced by prenatal exposure to VPA. Additionally, in vivo administration of LP-211 resulted in improvements in motor coordination, novel object recognition, and a reduction in stereotypic behaviors in autistic-like offspring. The findings suggest that dysregulated expression of 5-HT7Rs may play a role in the pathophysiology of ASD, and that agonists like LP-211 could potentially be explored as a pharmacological treatment for autism spectrum disorder.

Asunto(s)

Modelos Animales de Enfermedad , Efectos Tardíos de la Exposición Prenatal , Receptores de Serotonina , Regulación hacia Arriba , Ácido Valproico , Animales , Receptores de Serotonina/metabolismo , Ácido Valproico/farmacología , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Femenino , Regulación hacia Arriba/efectos de los fármacos , Masculino , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/efectos de los fármacos , Ratas , Piperazinas/farmacología , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/tratamiento farmacológico , Ratas Wistar , Trastorno Autístico/metabolismo , Trastorno Autístico/tratamiento farmacológico

Asunto(s)

Trastorno Autístico , Serotonina , Humanos , Femenino , Serotonina/metabolismo , Serotonina/genética , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Embarazo , Masculino , Polimorfismo de Nucleótido Simple , Adulto

RESUMEN

Ectonucleotidases play an important role in regulating the level of extracellular nucleotides and nucleosides and are an important part of the regulation of the effects of adenosine and ATP on adenosine and P2 receptors, respectively. We have previously established the ambiguous effect of P2 receptor agonists on the contractile activity of smooth muscle tissue in rats with the valproate model of autism. In this work, HPLC was used to evaluate the activity of ectonucleotidases in the smooth muscle tissues of the internal organs of rats with a valproate model of autism. The activity of ectonucleotidases was significantly higher in the smooth muscle tissues of the duodenum, vas deferens, and bladder, but lower in the ileum and uterus. The results obtained make it possible to compare the activity of ectonucleotidases identified here with changes in P2 receptor-mediated contractility of smooth muscle tissues revealed in our previous experiments.

Asunto(s)

Trastorno Autístico , Contracción Muscular , Músculo Liso , Vejiga Urinaria , Ácido Valproico , Conducto Deferente , Animales , Ratas , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Ácido Valproico/farmacología , Trastorno Autístico/metabolismo , Trastorno Autístico/inducido químicamente , Trastorno Autístico/tratamiento farmacológico , Masculino , Femenino , Conducto Deferente/efectos de los fármacos , Conducto Deferente/metabolismo , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/metabolismo , Vejiga Urinaria/enzimología , Contracción Muscular/efectos de los fármacos , Útero/efectos de los fármacos , Útero/metabolismo , Íleon/efectos de los fármacos , Íleon/metabolismo , Íleon/enzimología , Modelos Animales de Enfermedad , Ratas Wistar , Receptores Purinérgicos P2/metabolismo , Adenosina Trifosfatasas/metabolismo