Biological Psychiatry : Alterations in Cortical Development in Autism Spectrum Disorder (août 2017)

jeudi 10 août 2017

1. A brief summary of the articles appearing in this issue of Biological Psychiatry. Biological Psychiatry ;2017 (8/1/) ;82(3):151.

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2. Winterer G. Noisy Networks and Autism. Biological Psychiatry ;2017 (8/1/) ;82(3):152-154.

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3. Pelphrey K. Charting a Course for Autism Biomarkers. Biological Psychiatry ;2017 (8/1/) ;82(3):155-156.

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4. Lewis JD, Evans AC, Pruett Jr JR, Botteron KN, McKinstry RC, Zwaigenbaum L, Estes AM, Collins DL, Kostopoulos P, Gerig G, Dager SR, Paterson S, Schultz RT, Styner MA, Hazlett HC, Piven J, Piven J, Hazlett HC, Chappell C, Dager SR, Estes AM, Shaw D, Botteron KN, McKinstry RC, Constantino J, Pruett JR, Schultz RT, Paterson S, Zwaigenbaum L, Elison JT, Evans AC, Collins DL, Pike GB, Fonov V, Kostopoulos P, Das S, Gerig G, Styner MA, Gu H. The Emergence of Network Inefficiencies in Infants With Autism Spectrum Disorder. Biological Psychiatry ;2017 (8/1/) ;82(3):176-185.

AbstractBackground Autism spectrum disorder (ASD) is a developmental disorder defined by behavioral features that emerge during the first years of life. Research indicates that abnormalities in brain connectivity are associated with these behavioral features. However, the inclusion of individuals past the age of onset of the defining behaviors complicates interpretation of the observed abnormalities : they may be cascade effects of earlier neuropathology and behavioral abnormalities. Our recent study of network efficiency in a cohort of 24-month-olds at high and low familial risk for ASD reduced this confound ; we reported reduced network efficiencies in toddlers classified with ASD. The current study maps the emergence of these inefficiencies in the first year of life. Methods This study uses data from 260 infants at 6 and 12 months of age, including 116 infants with longitudinal data. As in our earlier study, we use diffusion data to obtain measures of the length and strength of connections between brain regions to compute network efficiency. We assess group differences in efficiency within linear mixed-effects models determined by the Akaike information criterion. Results Inefficiencies in high-risk infants later classified with ASD were detected from 6 months onward in regions involved in low-level sensory processing. In addition, within the high-risk infants, these inefficiencies predicted 24-month symptom severity. Conclusions These results suggest that infants with ASD, even before 6 months of age, have deficits in connectivity related to low-level processing, which contribute to a developmental cascade affecting brain organization and eventually higher-level cognitive processes and social behavior.

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5. Shen MD, Kim SH, McKinstry RC, Gu H, Hazlett HC, Nordahl CW, Emerson RW, Shaw D, Elison JT, Swanson MR, Fonov VS, Gerig G, Dager SR, Botteron KN, Paterson S, Schultz RT, Evans AC, Estes AM, Zwaigenbaum L, Styner MA, Amaral DG, Piven J, Piven J, Hazlett HC, Chappell C, Dager S, Estes A, Shaw D, Botteron K, McKinstry R, Constantino J, Pruett J, Schultz R, Zwaigenbaum L, Elison J, Evans AC, Collins DL, Pike GB, Fonov V, Kostopoulos P, Das S, Gerig G, Styner M, Gu H. Increased Extra-axial Cerebrospinal Fluid in High-Risk Infants Who Later Develop Autism. Biological Psychiatry ;2017 (8/1/) ;82(3):186-193.

AbstractBackground We previously reported that infants who developed autism spectrum disorder (ASD) had increased cerebrospinal fluid (CSF) in the subarachnoid space (i.e., extra-axial CSF) from 6 to 24 months of age. We attempted to confirm and extend this finding in a larger independent sample. Methods A longitudinal magnetic resonance imaging study of infants at risk for ASD was carried out on 343 infants, who underwent neuroimaging at 6, 12, and 24 months. Of these infants, 221 were at high risk for ASD because of an older sibling with ASD, and 122 were at low risk with no family history of ASD. A total of 47 infants were diagnosed with ASD at 24 months and were compared with 174 high-risk and 122 low-risk infants without ASD. Results Infants who developed ASD had significantly greater extra-axial CSF volume at 6 months compared with both comparison groups without ASD (18% greater than high-risk infants without ASD ; Cohen’s d = 0.54). Extra-axial CSF volume remained elevated through 24 months (d = 0.46). Infants with more severe autism symptoms had an even greater volume of extra-axial CSF from 6 to 24 months (24% greater at 6 months, d = 0.70 ; 15% greater at 24 months, d = 0.70). Extra-axial CSF volume at 6 months predicted which high-risk infants would be diagnosed with ASD at 24 months with an overall accuracy of 69% and corresponding 66% sensitivity and 68% specificity, which was fully cross-validated in a separate sample. Conclusions This study confirms and extends previous findings that increased extra-axial CSF is detectable at 6 months in high-risk infants who develop ASD. Future studies will address whether this anomaly is a contributing factor to the etiology of ASD or an early risk marker for ASD.

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6. Rapanelli M, Frick LR, Xu M, Groman SM, Jindachomthong K, Tamamaki N, Tanahira C, Taylor JR, Pittenger C. Targeted Interneuron Depletion in the Dorsal Striatum Produces Autism-like Behavioral Abnormalities in Male but Not Female Mice. Biological Psychiatry ;2017 (8/1/) ;82(3):194-203.

AbstractBackground Interneuronal pathology is implicated in many neuropsychiatric disorders, including autism spectrum disorder (ASD) and Tourette syndrome (TS). Interneurons of the striatum, including the parvalbumin-expressing fast-spiking interneurons (FSIs) and the large cholinergic interneurons (CINs), are affected in patients with TS and in preclinical models of both ASD and TS. Methods To test the causal importance of these neuronal abnormalities, we recapitulated them in vivo in developmentally normal mice using a combination transgenic–viral strategy for targeted toxin-mediated ablation. Results We found that conjoint 50% depletion of FSIs and CINs in the dorsal striatum of male mice produces spontaneous stereotypy and marked deficits in social interaction. Strikingly, these behavioral effects are not seen in female mice ; because ASD and TS have a marked male predominance, this observation reinforces the potential relevance of the finding to human disease. Neither of these effects is seen when only one or the other interneuronal population is depleted ; ablation of both is required. Depletion of FSIs, but not of CINs, also produces anxiety-like behavior, as has been described previously. Behavioral pathology in male mice after conjoint FSI and CIN depletion is accompanied by increases in activity-dependent signaling in the dorsal striatum ; these alterations were not observed after disruption of only one interneuron type or in doubly depleted female mice. Conclusions These data indicate that disruption of CIN and FSI interneurons in the dorsal striatum is sufficient to produce network and behavioral changes of potential relevance to ASD, in a sexually dimorphic manner.

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7. de Kovel CGF, Lisgo S, Karlebach G, Ju J, Cheng G, Fisher SE, Francks C. Left–Right Asymmetry of Maturation Rates in Human Embryonic Neural Development. Biological Psychiatry ;2017 (8/1/) ;82(3):204-212.

AbstractBackground Left–right asymmetry is a fundamental organizing feature of the human brain, and neuropsychiatric disorders such as schizophrenia sometimes involve alterations of brain asymmetry. As early as 8 weeks postconception, the majority of human fetuses move their right arms more than their left arms, but because nerve fiber tracts are still descending from the forebrain at this stage, spinal–muscular asymmetries are likely to play an important developmental role. Methods We used RNA sequencing to measure gene expression levels in the left and right spinal cords, and the left and right hindbrains, of 18 postmortem human embryos aged 4 to 8 weeks postconception. Genes showing embryonic lateralization were tested for an enrichment of signals in genome-wide association data for schizophrenia. Results The left side of the embryonic spinal cord was found to mature faster than the right side. Both sides transitioned from transcriptional profiles associated with cell division and proliferation at earlier stages to neuronal differentiation and function at later stages, but the two sides were not in synchrony (p = 2.2 E-161). The hindbrain showed a left–right mirrored pattern compared with the spinal cord, consistent with the well-known crossing over of function between these two structures. Genes that showed lateralization in the embryonic spinal cord were enriched for association signals with schizophrenia (p = 4.3 E-05). Conclusions These are the earliest stage left–right differences of human neural development ever reported. Disruption of the lateralized developmental program may play a role in the genetic susceptibility to schizophrenia.

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8. Michaelson JJ, Shin M-K, Koh J-Y, Brueggeman L, Zhang A, Katzman A, McDaniel L, Fang M, Pufall M, Pieper AA. Neuronal PAS Domain Proteins 1 and 3 Are Master Regulators of Neuropsychiatric Risk Genes. Biological Psychiatry ;2017 (8/1/) ;82(3):213-223.

AbstractBackground NPAS3 has been established as a robust genetic risk factor in major mental illness. In mice, loss of neuronal PAS domain protein 3 (NPAS3) impairs postnatal hippocampal neurogenesis, while loss of the related protein NPAS1 promotes it. These and other findings suggest a critical role for NPAS proteins in neuropsychiatric functioning, prompting interest in the molecular pathways under their control. Methods We used RNA sequencing coupled with chromatin immunoprecipitation sequencing to identify genes directly regulated by NPAS1 and NPAS3 in the hippocampus of wild-type, Npas1−/−, and Npas3−/− mice. Computational integration with human genetic and expression data revealed the disease relevance of NPAS-regulated genes and pathways. Specific findings were confirmed at the protein level by Western blot. Results This is the first in vivo, transcriptome-scale investigation of genes regulated by NPAS1 and NPAS3. These transcription factors control an ensemble of genes that are themselves also major regulators of neuropsychiatric function. Specifically, Fmr1 (fragile X syndrome) and Ube3a (Angelman syndrome) are transcriptionally regulated by NPAS3, as is the neurogenesis regulator Notch. Dysregulation of these pathways was confirmed at the protein level. Furthermore, NPAS1/3 targets show increased human genetic burden for schizophrenia and intellectual disability. Conclusions Together, these data provide a clear, unbiased view of the full spectrum of genes regulated by NPAS1 and NPAS3 and show that these transcription factors are master regulators of neuropsychiatric function. These findings expose the molecular pathophysiology of NPAS1/3 mutations and provide a striking example of the shared, combinatorial nature of molecular pathways that underlie diagnostically distinct neuropsychiatric conditions.

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9. Ben-Shalom R, Keeshen CM, Berrios KN, An JY, Sanders SJ, Bender KJ. Opposing Effects on NaV1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures. Biological Psychiatry ;2017 (8/1/) ;82(3):224-232.

AbstractBackground Variants in the SCN2A gene that disrupt the encoded neuronal sodium channel NaV1.2 are important risk factors for autism spectrum disorder (ASD), developmental delay, and infantile seizures. Variants observed in infantile seizures are predominantly missense, leading to a gain of function and increased neuronal excitability. How variants associated with ASD affect NaV1.2 function and neuronal excitability are unclear. Methods We examined the properties of 11 ASD-associated SCN2A variants in heterologous expression systems using whole-cell voltage-clamp electrophysiology and immunohistochemistry. Resultant data were incorporated into computational models of developing and mature cortical pyramidal cells that express NaV1.2. Results In contrast to gain of function variants that contribute to seizure, we found that all ASD-associated variants dampened or eliminated channel function. Incorporating these electrophysiological results into a compartmental model of developing excitatory neurons demonstrated that all ASD variants, regardless of their mechanism of action, resulted in deficits in neuronal excitability. Corresponding analysis of mature neurons predicted minimal change in neuronal excitability. Conclusions This functional characterization thus identifies SCN2A mutation and NaV1.2 dysfunction as the most frequently observed ASD risk factor detectable by exome sequencing and suggests that associated changes in neuronal excitability, particularly in developing neurons, may contribute to ASD etiology.

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