RESUMEN
Somatosensory over-reactivity is common among patients with autism spectrum disorders (ASDs) and is hypothesized to contribute to core ASD behaviors. However, effective treatments for sensory over-reactivity and ASDs are lacking. We found distinct somatosensory neuron pathophysiological mechanisms underlie tactile abnormalities in different ASD mouse models and contribute to some ASD-related behaviors. Developmental loss of ASD-associated genes Shank3 or Mecp2 in peripheral mechanosensory neurons leads to region-specific brain abnormalities, revealing links between developmental somatosensory over-reactivity and the genesis of aberrant behaviors. Moreover, acute treatment with a peripherally restricted GABAA receptor agonist that acts directly on mechanosensory neurons reduced tactile over-reactivity in six distinct ASD models. Chronic treatment of Mecp2 and Shank3 mutant mice improved body condition, some brain abnormalities, anxiety-like behaviors, and some social impairments but not memory impairments, motor deficits, or overgrooming. Our findings reveal a potential therapeutic strategy targeting peripheral mechanosensory neurons to treat tactile over-reactivity and select ASD-related behaviors.
Asunto(s)
Trastorno del Espectro Autista/metabolismo , Agonistas del GABA/farmacología , Ácidos Isonicotínicos/farmacología , Fenotipo , Células Receptoras Sensoriales/efectos de los fármacos , Tacto/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Ansiedad/tratamiento farmacológico , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Agonistas del GABA/uso terapéutico , Ácidos Isonicotínicos/uso terapéutico , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos , Proteínas del Tejido Nervioso/genética , Inhibición Prepulso/efectos de los fármacos , Células Receptoras Sensoriales/metabolismoRESUMEN
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder for which current treatments are limited and drug development costs are prohibitive. Identifying drug targets for ASD is crucial for the development of targeted therapies. Summary-level data of expression quantitative trait loci obtained from GTEx, protein quantitative trait loci data from the ROSMAP project, and two ASD genome-wide association studies datasets were utilized for discovery and replication. We conducted a combined analysis using Mendelian randomization (MR), transcriptome-wide association studies, Bayesian colocalization, and summary-data-based MR to identify potential therapeutic targets associated with ASD and examine whether there are shared causal variants among them. Furthermore, pathway and drug enrichment analyses were performed to further explore the underlying mechanisms and summarize the current status of pharmacological targets for developing drugs to treat ASD. The protein-protein interaction (PPI) network and mouse knockout models were performed to estimate the effect of therapeutic targets. A total of 17 genes revealed causal associations with ASD and were identified as potential targets for ASD patients. Cathepsin B (CTSB) [odd ratio (OR) = 2.66 95, confidence interval (CI): 1.28-5.52, P = 8.84 × 10-3], gamma-aminobutyric acid type B receptor subunit 1 (GABBR1) (OR = 1.99, 95CI: 1.06-3.75, P = 3.24 × 10-2), and formin like 1 (FMNL1) (OR = 0.15, 95CI: 0.04-0.58, P = 5.59 × 10-3) were replicated in the proteome-wide MR analyses. In Drugbank, two potential therapeutic drugs, Acamprosate (GABBR1 inhibitor) and Bryostatin 1 (CASP8 inhibitor), were inferred as potential influencers of autism. Knockout mouse models suggested the involvement of the CASP8, GABBR1, and PLEKHM1 genes in neurological processes. Our findings suggest 17 candidate therapeutic targets for ASD and provide novel drug targets for therapy development and critical drug repurposing opportunities.
Asunto(s)
Trastorno del Espectro Autista , Estudio de Asociación del Genoma Completo , Proteómica , Humanos , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Animales , Ratones , Transcriptoma , Sitios de Carácter Cuantitativo , Mapas de Interacción de Proteínas/efectos de los fármacos , Ratones Noqueados , Terapia Molecular DirigidaRESUMEN
Alterations in γ-aminobutyric acid (GABA) have been implicated in sensory differences in individuals with autism spectrum disorder (ASD). Visual signals are initially processed in the retina, and in this study, we explored the hypotheses that the GABA-dependent retinal response to light is altered in individuals with ASD. Light-adapted electroretinograms were recorded from 61 adults (38 males and 23 females; n = 22 ASD) in response to three stimulus protocols: (1) the standard white flash, (2) the standard 30â Hz flickering protocol, and (3) the photopic negative response protocol. Participants were administered an oral dose of placebo, 15 or 30â mg of arbaclofen (STX209, GABAB agonist) in a randomized, double-blind, crossover order before the test. At baseline (placebo), the a-wave amplitudes in response to single white flashes were more prominent in ASD, relative to typically developed (TD) participants. Arbaclofen was associated with a decrease in the a-wave amplitude in ASD, but an increase in TD, eliminating the group difference observed at baseline. The extent of this arbaclofen-elicited shift significantly correlated with the arbaclofen-elicited shift in cortical responses to auditory stimuli as measured by using an electroencephalogram in our prior study and with broader autistic traits measured with the autism quotient across the whole cohort. Hence, GABA-dependent differences in retinal light processing in ASD appear to be an accessible component of a wider autistic difference in the central processing of sensory information, which may be upstream of more complex autistic phenotypes.
Asunto(s)
Trastorno del Espectro Autista , Masculino , Adulto , Femenino , Humanos , Trastorno del Espectro Autista/tratamiento farmacológico , Retina , Electroencefalografía , Ácido gamma-Aminobutírico , ElectrorretinografíaRESUMEN
The use of antidepressants during pregnancy benefits the mother's well-being, but the effects of such substances on neurodevelopment remain poorly understood. Moreover, the consequences of early exposure to antidepressants may not be immediately apparent at birth. In utero exposure to selective serotonin reuptake inhibitors (SSRIs) has been related to developmental abnormalities, including a reduced white matter volume. Several reports have observed an increased incidence of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) after prenatal exposure to SSRIs such as sertraline, the most widely prescribed SSRI. The advent of human-induced pluripotent stem cell (hiPSC) methods and assays now offers appropriate tools to test the consequences of such compounds for neurodevelopment in vitro. In particular, hiPSCs can be used to generate cerebral organoids - self-organized structures that recapitulate the morphology and complex physiology of the developing human brain, overcoming the limitations found in 2D cell culture and experimental animal models for testing drug efficacy and side effects. For example, single-cell RNA sequencing (scRNA-seq) and electrophysiological measurements on organoids can be used to evaluate the impact of antidepressants on the transcriptome and neuronal activity signatures in developing neurons. While the analysis of large-scale transcriptomic data depends on dimensionality reduction methods, electrophysiological recordings rely on temporal data series to discriminate statistical characteristics of neuronal activity, allowing for the rigorous analysis of the effects of antidepressants and other molecules that affect the developing nervous system, especially when applied in combination with relevant human cellular models such as brain organoids.
Asunto(s)
Trastorno del Espectro Autista , Inhibidores Selectivos de la Recaptación de Serotonina , Embarazo , Femenino , Recién Nacido , Animales , Humanos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/epidemiología , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Encéfalo , OrganoidesRESUMEN
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading single-gene form of autism spectrum disorder, encompassing cognitive, behavioral, and physical forms of clinical involvement. FXS is caused by large expansions of a noncoding CGG repeat (>200 repeats) in the FMR1 gene, at which point the gene is generally silenced. Absence of FMR1 protein (FMRP), important for synaptic development and maintenance, gives rise to the neurodevelopmental disorder. There is, at present, no therapeutic approach that directly reverses the loss of FMRP; however, there is an increasing number of potential treatments that target the pathways dysregulated in FXS, including those that address the enhanced activity of the mGluR5 pathway and deficits in GABA pathways. Based on studies of targeted therapeutics to date, the prospects are good for one or more effective therapies for FXS in the near future.
Asunto(s)
Trastorno del Espectro Autista , Síndrome del Cromosoma X Frágil , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/uso terapéutico , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/metabolismo , HumanosRESUMEN
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders mainly characterized by deficient sociability and repetitive behaviors. Effective treatment for the core symptoms of ASD is still lacking. Behavioral interventions show limited effectiveness, while pharmacotherapy focuses on the amelioration of secondary symptomatology. Oxytocin (OXT) is a neuropeptide known for its prosocial impact, making it a candidate drug for ASD treatment. Its alleviating effect has been and still is widely researched, but outcomes reported by clinical studies are ambiguous. We examined the effect of daily intranasal OXT (0.8 IU/kg) administration for 4 weeks on the ASD-like phenotype in Shank3-/- adult mice. Animals treated with OXT spent twice as much time interacting with the social partner as early as after 2 weeks of treatment. Furthermore, OXT-treated mice exhibited reduced explorative behavior by 50%, after 4 weeks of treatment, and a 30% reduction in repetitive behavior, 4 weeks after treatment termination. One-fold higher sociability and 30% reduced exploration due to OXT lasted up to 4 weeks following the treatment termination. However, social disinterest was elevated by roughly 10% as well, indicating a form of social ambivalence. Obtained results support the therapeutic potential of intranasally administered OXT in alleviating social shortfalls in a genetic model of ASD. Subsequent research is necessary to elucidate the benefits and risks of the long-term OXT administration, as well as its applicability in other ASD models and the potential treatment effect on social communication, which was not measured in the present study.
Asunto(s)
Administración Intranasal , Trastorno del Espectro Autista , Modelos Animales de Enfermedad , Ratones Noqueados , Oxitocina , Conducta Social , Animales , Oxitocina/administración & dosificación , Oxitocina/farmacología , Administración Intranasal/métodos , Ratones , Masculino , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Proteínas del Tejido Nervioso/genética , Trastorno Autístico/genética , Trastorno Autístico/tratamiento farmacológico , Conducta Exploratoria/efectos de los fármacos , Proteínas de Microfilamentos/genética , Conducta Animal/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
The Shank3 gene encodes the major postsynaptic scaffolding protein SHANK3. Its mutation causes a syndromic form of autism spectrum disorder (ASD): Phelan-McDermid Syndrome (PMDS). It is characterized by global developmental delay, intellectual disorders (ID), ASD behavior, affective symptoms, as well as extra-cerebral symptoms. Although Shank3 deficiency causes a variety of molecular alterations, they do not suffice to explain all clinical aspects of this heterogenic syndrome. Since global gene expression alterations in Shank3 deficiency remain inadequately studied, we explored the transcriptome in vitro in primary hippocampal cells from Shank3∆11(-/-) mice, under control and lithium (Li) treatment conditions, and confirmed the findings in vivo. The Shank3∆11(-/-) genotype affected the overall transcriptome. Remarkably, extracellular matrix (ECM) and cell cycle transcriptional programs were disrupted. Accordingly, in the hippocampi of adolescent Shank3∆11(-/-) mice we found proteins of the collagen family and core cell cycle proteins downregulated. In vitro Li treatment of Shank3∆11(-/-) cells had a rescue-like effect on the ECM and cell cycle gene sets. Reversed ECM gene sets were part of a network, regulated by common transcription factors (TF) such as cAMP responsive element binding protein 1 (CREB1) and ß-Catenin (CTNNB1), which are known downstream effectors of synaptic activity and targets of Li. These TFs were less abundant and/or hypo-phosphorylated in hippocampi of Shank3∆11(-/-) mice and could be rescued with Li in vitro and in vivo. Our investigations suggest the ECM compartment and cell cycle genes as new players in the pathophysiology of Shank3 deficiency, and imply involvement of transcriptional regulators, which can be modulated by Li. This work supports Li as potential drug in the management of PMDS symptoms, where a Phase III study is ongoing.
Asunto(s)
Matriz Extracelular , Hipocampo , Ratones Noqueados , Proteínas del Tejido Nervioso , beta Catenina , Animales , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Hipocampo/metabolismo , Matriz Extracelular/metabolismo , Ratones , beta Catenina/metabolismo , beta Catenina/genética , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/metabolismo , Deleción Cromosómica , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Cromosomas Humanos Par 22/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Masculino , Transcriptoma/genética , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/tratamiento farmacológico , Ratones Endogámicos C57BL , Litio/farmacología , Proteínas de Microfilamentos/metabolismo , Proteínas de Microfilamentos/genética , Células CultivadasRESUMEN
BACKGROUND: Experimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder. METHODS: We conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ. RESULTS: Of the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was -3.7 in the oxytocin group and -3.5 in the placebo group (least-squares mean difference, -0.2; 95% confidence interval, -1.5 to 1.0; P = 0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: This placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks. (Funded by the National Institute of Child Health and Human Development; SOARS-B ClinicalTrials.gov number, NCT01944046.).
Asunto(s)
Trastorno del Espectro Autista/tratamiento farmacológico , Oxitocina/administración & dosificación , Conducta Social , Administración Intranasal , Adolescente , Trastorno del Espectro Autista/psicología , Niño , Preescolar , Método Doble Ciego , Femenino , Humanos , Análisis de los Mínimos Cuadrados , Masculino , Oxitocina/efectos adversos , Oxitocina/uso terapéutico , Habilidades Sociales , Insuficiencia del TratamientoRESUMEN
Although oxytocin may provide a novel therapeutics for the core features of autism spectrum disorder (ASD), previous results regarding the efficacy of repeated or higher dose oxytocin are controversial, and the underlying mechanisms remain unclear. The current study is aimed to clarify whether repeated oxytocin alter plasma cytokine levels in relation to clinical changes of autism social core feature. Here we analyzed cytokine concentrations using comprehensive proteomics of plasmas of 207 adult males with high-functioning ASD collected from two independent multi-center large-scale randomized controlled trials (RCTs): Testing effects of 4-week intranasal administrations of TTA-121 (A novel oxytocin spray with enhanced bioavailability: 3U, 6U, 10U, or 20U/day) and placebo in the crossover discovery RCT; 48U/day Syntocinon or placebo in the parallel-group verification RCT. Among the successfully quantified 17 cytokines, 4 weeks TTA-121 6U (the peak dose for clinical effects) significantly elevated IL-7 (9.74, 95 % confidence interval [CI] 3.59 to 15.90, False discovery rate corrected P (PFDR) < 0.001), IL-9 (56.64, 20.46 to 92.82, PFDR < 0.001) and MIP-1b (18.27, 4.96 to 31.57, PFDR < 0.001) compared with placebo. Inverted U-shape dose-response relationships peaking at TTA-121 6U were consistently observed for all these cytokines (IL-7: P < 0.001; IL-9: P < 0.001; MIP-1b: P = 0.002). Increased IL-7 and IL-9 in participants with ASD after 4 weeks TTA-121 6U administration compared with placebo was verified in the confirmatory analyses in the dataset before crossover (PFDR < 0.001). Furthermore, the changes in all these cytokines during 4 weeks of TTA-121 10U administration revealed associations with changes in reciprocity score, the original primary outcome, observed during the same period (IL-7: Coefficient = -0.05, -0.10 to 0.003, P = 0.067; IL-9: -0.01, -0.02 to -0.003, P = 0.005; MIP-1b: -0.02, -0.04 to -0.007, P = 0.005). These findings provide the first evidence for a role of interaction between oxytocin and neuroinflammation in the change of ASD core social features, and support the potential role of this interaction as a novel therapeutic seed. Trial registration: UMIN000015264, NCT03466671/UMIN000031412.
Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Adulto , Masculino , Humanos , Oxitocina , Trastorno Autístico/tratamiento farmacológico , Citocinas , Interleucina-7 , Interleucina-9/uso terapéutico , Método Doble Ciego , Trastorno del Espectro Autista/tratamiento farmacológico , Administración Intranasal , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that severely affects individuals' daily life and social development. Unfortunately, there are currently no effective treatments for ASD. Dexmedetomidine (DEX) is a selective agonist of α2 adrenergic receptor (α2AR) and is widely used as a first-line medication for sedation and hypnosis in clinical practice. In recent years, there have been reports suggesting its potential positive effects on improving emotional and cognitive functions. However, whether dexmedetomidine has therapeutic effects on the core symptoms of ASD, namely social deficits and repetitive behaviors, remains to be investigated. In the present study, we employed various behavioral tests to assess the phenotypes of animals, including the three-chamber, self-grooming, marble burying, open field, and elevated plus maze. Additionally, electrophysiological recordings, western blotting, qPCR were mainly used to investigate and validate the potential mechanisms underlying the role of dexmedetomidine. We found that intraperitoneal injection of dexmedetomidine in ASD model mice-BTBR T+ Itpr3tf/J (BTBR) mice could adaptively improve their social deficits. Further, we observed a significant reduction in c-Fos positive signals and interleukin-6 (IL-6) expression level in the prelimbic cortex (PrL) of the BTBR mice treated with dexmedetomidine. Enhancing or inhibiting the action of IL-6 directly affects the social behavior of BTBR mice. Mechanistically, we have found that NF-κB p65 is a key pathway regulating IL-6 expression in the PrL region. In addition, we have confirmed that the α2AR acts as a receptor switch mediating the beneficial effects of dexmedetomidine in improving social deficits. This study provides the first evidence of the beneficial effects of dexmedetomidine on core symptoms of ASD and offers a theoretical basis and potential therapeutic approach for the clinical treatment of ASD.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2 , Trastorno del Espectro Autista , Dexmedetomidina , Modelos Animales de Enfermedad , Interleucina-6 , FN-kappa B , Receptores Adrenérgicos alfa 2 , Conducta Social , Animales , Dexmedetomidina/farmacología , Ratones , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/metabolismo , Masculino , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , FN-kappa B/metabolismo , Interleucina-6/metabolismo , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BL , Conducta Animal/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Inflamación/metabolismo , Inflamación/tratamiento farmacológicoRESUMEN
Early supports to enhance social development in children with autism are widely promoted. While oxytocin has a crucial role in mammalian social development, its potential role as a medication to enhance social development in humans remains unclear. We investigated the efficacy, tolerability, and safety of intranasal oxytocin in young children with autism using a double-blind, randomized, placebo-controlled, clinical trial, following a placebo lead-in phase. A total of 87 children (aged between 3 and 12 years) with autism received 16 International Units (IU) of oxytocin (n = 45) or placebo (n = 42) nasal spray, morning and night (32 IU per day) for twelve weeks, following a 3-week placebo lead-in phase. Overall, there was no effect of oxytocin treatment over time on the caregiver-rated Social Responsiveness Scale (SRS-2) (p = 0.686). However, a significant interaction with age (p = 0.028) showed that for younger children, aged 3-5 years, there was some indication of a treatment effect. Younger children who received oxytocin showed improvement on caregiver-rated social responsiveness ( SRS-2). There was no other evidence of benefit in the sample as a whole, or in the younger age group, on the clinician-rated Clinical Global Improvement Scale (CGI-S), or any secondary measure. Importantly, placebo effects in the lead-in phase were evident and there was support for washout of the placebo response in the randomised phase. Oxytocin was well tolerated, with more adverse side effects reported in the placebo group. This study suggests the need for further clinical trials to test the benefits of oxytocin treatment in younger populations with autism.Trial registration www.anzctr.org.au (ACTRN12617000441314).
Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Niño , Preescolar , Humanos , Administración Intranasal , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno Autístico/tratamiento farmacológico , Método Doble Ciego , Rociadores Nasales , Oxitocina/farmacología , Oxitocina/uso terapéutico , Interacción Social , Resultado del TratamientoRESUMEN
MYT1L is an autism spectrum disorder (ASD)-associated transcription factor that is expressed in virtually all neurons throughout life. How MYT1L mutations cause neurological phenotypes and whether they can be targeted remains enigmatic. Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice exhibit neurodevelopmental delays with thinner cortices, behavioural phenotypes, and gene expression changes that resemble those of ASD patients. MYT1L target genes, including WNT and NOTCH, are activated upon MYT1L depletion and their chemical inhibition can rescue delayed neurogenesis in vitro. MYT1L deficiency also causes upregulation of the main cardiac sodium channel, SCN5A, and neuronal hyperactivity, which could be restored by shRNA-mediated knockdown of SCN5A or MYT1L overexpression in postmitotic neurons. Acute application of the sodium channel blocker, lamotrigine, also rescued electrophysiological defects in vitro and behaviour phenotypes in vivo. Hence, MYT1L mutation causes both developmental and postmitotic neurological defects. However, acute intervention can normalise resulting electrophysiological and behavioural phenotypes in adulthood.
Asunto(s)
Trastorno del Espectro Autista , Animales , Humanos , Ratones , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Trastorno Autístico/tratamiento farmacológico , Trastorno Autístico/genética , Haploinsuficiencia/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Fenotipo , Factores de Transcripción/genéticaRESUMEN
Pitt Hopkins Syndrome (PTHS) is a rare syndromic form of autism spectrum disorder (ASD) caused by autosomal dominant mutations in the Transcription Factor 4 (TCF4) gene. TCF4 is a basic helix-loop-helix transcription factor that is critical for neurodevelopment and brain function through its binding to cis-regulatory elements of target genes. One potential therapeutic strategy for PTHS is to identify dysregulated target genes and normalize their dysfunction. Here, we propose that SCN10A is an important target gene of TCF4 that is an applicable therapeutic approach for PTHS. Scn10a encodes the voltage-gated sodium channel Nav1.8 and is consistently shown to be upregulated in PTHS mouse models. In this perspective, we review prior literature and present novel data that suggests inhibiting Nav1.8 in PTHS mouse models is effective at normalizing neuron function, brain circuit activity and behavioral abnormalities and posit this therapeutic approach as a treatment for PTHS.
Asunto(s)
Discapacidad Intelectual , Canal de Sodio Activado por Voltaje NAV1.8 , Animales , Ratones , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Facies , Hiperventilación/genética , Discapacidad Intelectual/tratamiento farmacológico , Discapacidad Intelectual/genética , Discapacidad Intelectual/metabolismo , Factor de Transcripción 4/genética , Canal de Sodio Activado por Voltaje NAV1.8/química , Canal de Sodio Activado por Voltaje NAV1.8/metabolismoRESUMEN
Clinical trials of pharmacological candidates targeting the core features of autism have largely failed. This is despite evidence linking differences in multiple neurochemical systems to brain function in autism. While this has in part been explained by the heterogeneity of the autistic population, the field has largely relied upon association studies to link brain chemistry to function. The only way to directly establish that a neurotransmitter or neuromodulator is involved in a candidate brain function is to change it and observe a shift in that function. This experimental approach dominates preclinical neuroscience, but not human studies. There is little direct experimental evidence describing how neurochemical systems modulate information processing in the living human brain. Thus, our understanding of how neurochemical differences contribute to neurodiversity is limited, impeding our ability to translate findings from animal studies into humans. Here, we introduce our 'shiftability' paradigm, an approach to bridge the translational gap in autism research. We provide an overview of the guiding principles and methodologies we use to directly test the hypothesis that neurochemical systems function differently in autistic and non-autistic individuals.
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Investigación Biomédica Traslacional , Humanos , Trastorno Autístico/fisiopatología , Neurociencias , Trastorno del Espectro Autista/fisiopatología , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/metabolismo , Animales , Encéfalo/fisiopatología , Encéfalo/metabolismoRESUMEN
INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting approximately 3% of school-age children. The core symptoms are deficits in social communication and restricted and repetitive patterns of behavior. Associated problems in cognition, language, behavior, sleep and mood are prevalent. Currently, no established pharmacological treatment exists for core ASD symptoms. Risperidone and aripiprazole are used to manage associated irritability, but their effectiveness is limited and adverse events are common. AREAS COVERED: This mini-review summarizes existing scientific literature and ongoing clinical trials concerning cannabinoid treatment for ASD. Uncontrolled case series have documented improvements in both core ASD symptoms and related behavioral challenges in children treated with cannabis extracts rich in cannabidiol (CBD). Placebo-controlled studies involving CBD-rich cannabis extracts and/or pure CBD in children with ASD have demonstrated mixed efficacy results. A similar outcome was observed in a placebo-controlled study of pure CBD addressing social avoidance in Fragile X syndrome. Importantly, these studies have shown relatively high safety and tolerability. EXPERT OPINION: While current clinical data suggest the potential of CBD and CBD-rich cannabis extract in managing core and behavioral deficits in ASD, it is prudent to await the results of ongoing placebo-controlled trials before considering CBD treatment for ASD.
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Trastorno del Espectro Autista , Cannabinoides , Niño , Humanos , Aripiprazol/efectos adversos , Trastorno del Espectro Autista/tratamiento farmacológico , Cannabidiol/uso terapéutico , Cannabinoides/uso terapéutico , Genio Irritable , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
INTRODUCTION: Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million. Irritability is a challenging behavior associated with ASD, for which medication development has lagged. More specifically, pharmacotherapy effectiveness may be limited against high adverse effects (considering side effect profiles and patient medication sensitivity); thus, the possible benefits of pharmacological interventions must be balanced against potential adverse events in each patient. AREAS COVERED: After reviewing the neuropathophysiology of ASD-associated irritability, the benefits and tolerability of emerging medications in its treatment based on randomized controlled trials were detailed in light of mechanisms and targets of action. EXPERT OPINION: Succeeding risperidone and aripiprazole, monotherapy with memantine may be beneficial. In addition, N-acetylcysteine, galantamine, sulforaphane, celecoxib, palmitoylethanolamide, pentoxifylline, simvastatin, minocycline, amantadine, pregnenolone, prednisolone, riluzole, propentofylline, pioglitazone, and topiramate, all adjunct to risperidone, and clonidine and methylphenidate outperformed placebo. These effects were through glutamatergic, γ-aminobutyric acidergic, inflammatory, oxidative, cholinergic, dopaminergic, and serotonergic systems. All medications were reported to be safe and tolerable. Considering sample size, follow-up, and effect size, further studies are necessary. Along with drug development, repositioning and combining existing drugs supported by the mechanism of action is recommended.
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Antipsicóticos , Trastorno del Espectro Autista , Niño , Humanos , Risperidona/efectos adversos , Antipsicóticos/efectos adversos , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/inducido químicamente , Aripiprazol/uso terapéutico , RiluzolRESUMEN
BACKGROUND: Risperidone is an atypical antipsychotic drug used to treat irritability and aggression in children and adolescents with autism spectrum disorder. In an earlier study, the sum trough concentration of risperidone and its metabolite (9-hydroxyrisperidone) was positively correlated with weight gain and effectiveness. The aim of this study was to determine the therapeutic window for risperidone sum trough concentrations that balances weight gain with treatment effectiveness in this population. In addition, the effect of therapeutic drug monitoring (TDM) on treatment optimization was simulated. METHODS: In a retrospective cohort (n = 24 children), the target window for risperidone leading to the least increase in body mass index z-scores while retaining effectiveness as measured by the irritability subscale of the Aberrant Behavior Checklist was determined using receiver operating curve analysis. This target range was used to simulate the effect of TDM using a population PK model implemented in the software platform InsightRX. Dosing advice was based on plasma trough concentrations and the dose administered at 12 weeks to simulate whether more children would be on target at 24 weeks after the start of treatment. RESULTS: A risperidone sum trough target range of 3.5-7.0 mcg/L would minimize increase in body mass index z-score and optimize effectiveness. Dosing advice using TDM and a population PK model would lead to a larger proportion of children achieving the target concentration range (62.5% versus 16.7%). CONCLUSIONS: TDM may be a useful tool for optimizing risperidone treatment in children and adolescents with autism spectrum disorder.
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Antipsicóticos , Trastorno del Espectro Autista , Niño , Adolescente , Humanos , Risperidona/uso terapéutico , Trastorno del Espectro Autista/tratamiento farmacológico , Estudios Retrospectivos , Monitoreo de Drogas , Antipsicóticos/uso terapéutico , Aumento de Peso , Resultado del TratamientoRESUMEN
OBJECTIVE: The authors sought to explore the role of iron supplementation in the management of neurodevelopmental disorders among children and youths. METHODS: A systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was undertaken. A subset of results was suitable for meta-analysis. The quality of the evidence and strength of the clinical recommendations were assessed by using the Grading of Recommendations, Assessment, Development, and Evaluation method, and critical appraisal was conducted with the Joanna Briggs Institute critical appraisal tools. RESULTS: Nine articles met inclusion criteria. These articles included studies of attention-deficit hyperactivity disorder (ADHD) (N=7), autism spectrum disorder (N=1), and Tourette's syndrome (N=1). Three randomized controlled trials evaluating iron supplementation for ADHD hyperactivity symptom severity (124 participants: placebo, N=56; supplement, N=68) met inclusion criteria for a meta-analysis. Effect sizes for the placebo and supplement groups were moderate (Cohen's d=0.76) and large (Cohen's d=1.70), respectively, although these differences were not significant. The impact of iron supplementation on inattentive ADHD symptom severity was examined in two trials (75 participants: placebo, N=31; supplement, N=44). Large, nonsignificant effect sizes were demonstrated for the placebo (Cohen's d=1.66) and supplementation (Cohen's d=3.19) groups. The quality of the evidence and strength of the clinical recommendations were considered very low. CONCLUSIONS: Further research is needed to examine the role of iron supplementation in the management of ADHD and neurodevelopmental disorders more generally. Additionally, iron supplementation comes with risks, including death in the case of overdose.
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Suplementos Dietéticos , Trastornos del Neurodesarrollo , Humanos , Hierro/administración & dosificación , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Niño , Trastorno del Espectro Autista/tratamiento farmacológico , AdolescenteRESUMEN
BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, a limited range of activities, and deficiencies in social communications. Bone marrow mesenchymal stem cells (BM-MSCs), which secrete factors that stimulate surrounding microenvironment, and BM-MSCs conditioned medium (BM-MSCs-CM), which contains cell-secreted products, have been speculated to hold potential as a therapy for ASD. This study aimed to compare the therapeutic effects of BM-MSCs and BM-MSCs-CM on behavioral and microglial changes in an animal model of autism induced by valproic acid (VPA). METHODS AND RESULTS: Pregnant Wistar rats were administered by VPA at a dose of 600 mg/kg at 12.5 days post-conception. After birth, male pups were included in the study. At 6 weeks of age, one group of rats received intranasal administration of BM-MSCs, while another group received BM-MSCs-CM. The rats were allowed to recover for 2 weeks. Behavioral tests, quantitative real-time polymerase chain reaction (qRT-PCR), and immunohistochemistry were performed. Both BM-MSCs and BM-MSCs-CM administration significantly improved some behavioral deficits. Furthermore, these treatments notably reduced Iba-1 marker associated with microgliosis. Additionally, there was a significant reduction in the expression of pro-inflammatory cytokines IL-1ß and IL-6, and an increase in the levels of the anti-inflammatory cytokine IL-10 in rats administered by BM-MSCs and BM-MSCs-CM. CONCLUSIONS: Post-developmental administration of BM-MSCs and BM-MSCs-CM can ameliorate prenatal neurodevelopmental deficits, restore cognitive and social behaviors, and modulate microglial and inflammatory markers. Results indicated that the improvement rate was higher in the BM-MSCs group than BM-MSCs-CM group.
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Trastorno del Espectro Autista , Trastorno Autístico , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Embarazo , Femenino , Ratas , Masculino , Animales , Ácido Valproico/farmacología , Ácido Valproico/metabolismo , Medios de Cultivo Condicionados/farmacología , Medios de Cultivo Condicionados/metabolismo , Trastorno Autístico/inducido químicamente , Trastorno Autístico/terapia , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/tratamiento farmacológico , Ratas Wistar , Células Madre Mesenquimatosas/metabolismo , Citocinas/metabolismo , Trasplante de Células Madre Mesenquimatosas/métodos , Células de la Médula Ósea/metabolismoRESUMEN
Pitt-Hopkins syndrome is an autism spectrum disorder caused by autosomal dominant mutations in the human transcription factor 4 gene (TCF4). One pathobiological process caused by murine Tcf4 mutation is a cell autonomous reduction in oligodendrocytes and myelination. In this study, we show that the promyelinating compounds, clemastine, sobetirome and Sob-AM2 are effective at restoring myelination defects in a Pitt-Hopkins syndrome mouse model. In vitro, clemastine treatment reduced excess oligodendrocyte precursor cells and normalized oligodendrocyte density. In vivo, 2-week intraperitoneal administration of clemastine also normalized oligodendrocyte precursor cell and oligodendrocyte density in the cortex of Tcf4 mutant mice and appeared to increase the number of axons undergoing myelination, as EM imaging of the corpus callosum showed a significant increase in the proportion of uncompacted myelin and an overall reduction in the g-ratio. Importantly, this treatment paradigm resulted in functional rescue by improving electrophysiology and behaviour. To confirm behavioural rescue was achieved via enhancing myelination, we show that treatment with the thyroid hormone receptor agonist sobetirome or its brain penetrating prodrug Sob-AM2, was also effective at normalizing oligodendrocyte precursor cell and oligodendrocyte densities and behaviour in the Pitt-Hopkins syndrome mouse model. Together, these results provide preclinical evidence that promyelinating therapies may be beneficial in Pitt-Hopkins syndrome and potentially other neurodevelopmental disorders characterized by dysmyelination.