Serum levels of glial fibrillary acidic protein and Nogo-A in children with autism spectrum disorders

Context: Improved biomarkers would facilitate the diagnosis and treatment of autism spectrum disorders (ASD).

Objective: Our objective was to examine the levels of Nogo-A and glial fibrillary acidic protein (GFAP) in children with ASD.

Materials and methods: Serum concentrations of GFAP and Nogo-A were determined by enzyme-linked immunosorbent assay.

Results: In this preliminary study, we found that serum Nogo-A was not found significantly different between groups, while serum levels of GFAP were significantly lower in ASD than controls.

Discussion and conclusions: It will be of great interest to determine other potential causes of elevated serum levels of GFAP, and whether this elevation has any phenotypic effect.     

Autism in infants: an update

Although autism is a disorder of very early onset, knowledge on how it is first expressed in infancy has, until recently, remained limited. In recent years new strategies of research, including prospective studies, have substantially increased our knowledge regarding autism in infants. Research findings have suggested the very early emergence of significant differences in social information processes. In addition to having important implications for research, these findings also offer new opportunities for screening and early identification and, hopefully, for improved outcome.     

Social behavior in a genetic model of dopamine dysfunction at different neurodevelopmental time points

Impairments in social behavior characterize many neurodevelopmental psychiatric disorders. In fact, the temporal emergence and trajectory of these deficits can define the disorder, specify their treatment and signal their prognosis. The sophistication of mouse models with neurobiological endophenotypes of many aspects of psychiatric diseases has increased in recent years, with the necessity to evaluate social behavior in these models. We adapted an assay for the multimodal characterization of social behavior at different development time points (juvenile, adolescent and adult) in control mice in different social contexts (specifically, different sex pairings). Although social context did not affect social behavior in juvenile mice, it did have an effect on the quantity and type of social interaction as well as ultrasonic vocalizations in both adolescence and adulthood. We compared social development in control mice to a transgenic mouse model of the increase in postsynaptic striatal D2R activity observed in patients with schizophrenia (D2R‐OE mice). Genotypic differences in social interactions emerged in adolescence and appeared to become more pronounced in adulthood. That vocalizations emitted from dyads with a D2R‐OE subject were negatively correlated with active social behavior while vocalizations from control dyads were positively correlated with both active and passive social behavior also suggest social deficits. These data show that striatal dopamine dysfunction plays an important role in the development of social behavior and mouse models such as the one studied here provide an opportunity for screening potential therapeutics at different developmental time points.     

High affinity neurexin binding to cell adhesion G-protein-coupled receptor CIRL1/latrophilin-1 produces an intercellular adhesion complex

The G-protein-coupled receptor CIRL1/latrophilin-1 (CL1) and the type-1 membrane proteins neurexins represent distinct neuronal cell adhesion molecules that exhibit no similarities except for one common function: both proteins are receptors for α-latrotoxin, a component of black widow spider venom that induces massive neurotransmitter release at synapses. Unexpectedly, we have now identified a direct binding interaction between the extracellular domains of CL1 and neurexins that is regulated by alternative splicing of neurexins at splice site 4 (SS4). Using saturation binding assays, we showed that neurexins lacking an insert at SS4 bind to CL1 with nanomolar affinity, whereas neurexins containing an insert at SS4 are unable to bind. CL1 competed for neurexin binding with neuroligin-1, a well characterized neurexin ligand. The extracellular sequences of CL1 contain five domains (lectin, olfactomedin-like, serine/threonine-rich, hormone-binding, and G-protein-coupled receptor autoproteolysis-inducing (GAIN) domains). Of these domains, the olfactomedin-like domain mediates neurexin binding as shown by deletion mapping. Cell adhesion assays using cells expressing neurexins and CL1 revealed that their interaction produces a stable intercellular adhesion complex, indicating that their interaction can be trans-cellular. Thus, our data suggest that CL1 constitutes a novel ligand for neurexins that may be localized postsynaptically based on its well characterized interaction with intracellular SH3 and multiple ankyrin repeats adaptor proteins (SHANK) and could form a trans-synaptic complex with presynaptic neurexins.     

The neurobeachin gene spans the common fragile site FRA13A

Common fragile sites are normal constituents of chromosomal structure prone to chromosomal breakage. In humans, the cytogenetic locations of more than 80 common fragile sites are known. The DNA at 11 of them has been defined and characterized at the molecular level. According to the Genome Database, the common fragile site FRA13A maps to chromosome band 13q13.2. Here, we identify the precise genomic position of FRA13A, and characterize the genetic complexity of the fragile DNA sequence. We show that FRA13A breaks are limited to a 650 kb region within the neurobeachin (NBEA) gene, which genomically spans approximately 730 kb. NBEA encodes a neuron-specific multidomain protein implicated in membrane trafficking that is predominantly expressed in the brain and during development.     

Analysis of serotonin receptor 2A gene (HTR2A): Association study with autism spectrum disorder in the Indian population and investigation of the gene expression in peripheral blood leukocytes

Several studies suggest involvement of serotoninergic system in the pathophysiology of Autism Spectrum Disorder (ASD). The 5-HT receptor binding studies using ³H-lysergic acid diethylamide (³H-LSD) and linkage analysis provided evidences to consider HTR2A as a potential candidate gene for ASD. The three SNPs, −1438A/G (rs6311), 102T/C (rs6313) and 1354C/T (rs6314) of HTR2A have been well studied in the etiology of various neuropsychiatric disorders. But studies on association of this gene with ASD are limited to two reports from American and Korean populations. Additionally there are reports, which demonstrated paternal imprinting of HTR2A with expression from only one allele. So far no reports are available on HTR2A and its association with any neuropsychiatric disorders from Indian population. Therefore, the present study investigates association of the above mentioned three markers of HTR2A with ASD in Indian population using population and family-based approaches. The study also deals with allelic expression pattern of HTR2A in Peripheral Blood Leukocytes (PBLs) to understand the parental imprinting status. The genotyping analyses were carried out for probands, parents and controls. The subsequent association analyses did not show association of these markers with ASD. So, HTR2A is unlikely to be a genetic marker for ASD in Indian population. The expression analyses showed absence of monoallelic expression, suggesting lack of parental imprinting of HTR2A gene. However, we noticed methylation of the CpG sites at −1438A/G and 102T/C loci of HTR2A gene. Further bioinformatics analysis revealed absence of CpG islands in the promoter of the gene supporting biallelic expression pattern of HTR2A in PBLs.     

Event-related Potential Study of Novelty Processing Abnormalities in Autism

To better understand visual processing abnormalities in autism we studied the attention orienting related frontal event potentials (ERP) and the sustained attention related centro-parietal ERPs in a three stimulus oddball experiment. The three stimulus oddball paradigm was aimed to test the hypothesis that individuals with autism abnormally orient their attention to novel distracters as compared to controls. A dense-array 128 channel EGI electroencephalographic (EEG) system was used on 11 high-functioning children and young adults with autism spectrum disorder (ASD) and 11 age-matched, typically developing control subjects. Patients with ASD showed slower reaction times but did not differ in response accuracy. At the anterior (frontal) topography the ASD group showed significantly higher amplitudes and longer latencies of early ERP components (e.g., P100, N100) to novel distracter stimuli in both hemispheres. The ASD group also showed prolonged latencies of late ERP components (e.g., P2a, N200, P3a) to novel distracter stimuli in both hemispheres. However, differences were more profound in the right hemisphere for both early and late ERP components. Our results indicate augmented and prolonged early frontal potentials and a delayed P3a component to novel stimuli, which suggest low selectivity in pre-processing and later-stage under-activation of integrative regions in the prefrontal cortices. Also, at the posterior (centro-parietal) topography the ASD group showed significantly prolonged N100 latencies and reduced amplitudes of the N2b component to target stimuli. In addition, the latency of the P3b component was prolonged to novel distracters in the ASD group. In general, the autistic group showed prolonged latencies to novel stimuli especially in the right hemisphere. These results suggest that individuals with autism over-process information needed for the successful differentiation of target and novel stimuli. We propose the potential application of ERP evaluations in a novelty task as outcome measurements in the biobehavioral treatment (e.g., EEG biofeedback, TMS) of autism.     

Increased BDNF levels and NTRK2 gene association suggest a disruption of BDNF/TrkB signaling in autism

The brain‐derived neurotrophic factor (BDNF), a neurotrophin fundamental for brain development and function, has previously been implicated in autism. In this study, the levels of BDNF in platelet‐rich plasma were compared between autistic and control children, and the role of two genetic factors that might regulate this neurotrophin and contribute to autism etiology, BDNF and NTRK2, was examined. We found that BDNF levels in autistic children (n = 146) were significantly higher (t = 6.82; P < 0.0001) than in control children (n = 50) and were positively correlated with platelet serotonin distribution (r = 0.22; P = 0.004). Heritability of BDNF was estimated at 30% and therefore candidate genes BDNF and NTRK2 were tested for association with BDNF level distribution in this sample, and with autism in 469 trio families. Genetic association analysis provided no evidence for BDNF or NTRK2 as major determinants of the abnormally increased BDNF levels in autistic children. A significant association with autism was uncovered for six single nucleotide polymorphisms (SNPs) [0.004 (Z_(1df) = 2.85) < P < 0.039 (Z_(1df) = 2.06)] and multiple haplotypes [5 × 10^?4(χ_(3df) = 17.77) < P < 0.042 (χ_(9df) = 17.450)] in the NTRK2 gene. These results do not withstand correction for multiple comparisons, however, reflect a trend toward association that supports a role of NTRK2 as a susceptibility factor for the disorder. Genetic variation in the BDNF gene had no impact on autism risk. By substantiating the previously observed increase in BDNF levels in autistic children in a larger patient set, and suggesting a genetic association between NTRK2 and autism, this study integrates evidence from multiple levels supporting the hypothesis that alterations in BDNF/tyrosine kinase B (TrkB) signaling contribute to an increased vulnerability to autism.