Delling JP, Bauer HF, Gerlach-Arbeiter S, Schön M, Jacob C, Wagner J, Pedro MT, Knöll B, Boeckers TM.

Mol Psychiatry. 2024 Apr 22. doi: 10.1038/s41380-024-02559-9. Online ahead of print.

ABSTRACT

Synaptic dysfunction is a key feature of SHANK-associated disorders such as autism spectrum disorder, schizophrenia, and Phelan-McDermid syndrome. Since detailed knowledge of their effect on synaptic nanostructure remains limited, we aimed to investigate such alterations in ex11|SH3 SHANK3-KO mice combining expansion and STED microscopy. This enabled high-resolution imaging of mosaic-like arrangements formed by synaptic proteins in both human and murine brain tissue. We found distinct shape-profiles as fingerprints of the murine postsynaptic scaffold across brain regions and genotypes, as well as alterations in the spatial and molecular organization of subsynaptic domains under SHANK3-deficient conditions. These results provide insights into synaptic nanostructure in situ and advance our understanding of molecular mechanisms underlying synaptic dysfunction in neuropsychiatric disorders.

PMID:38649753 | DOI:10.1038/s41380-024-02559-9

Riemersma IW, Ike KGO, Sollie T, Meijer EL, Havekes R, Kas MJH.

Cereb Cortex. 2024 Apr 1;34(4):bhae136. doi: 10.1093/cercor/bhae136.

ABSTRACT

Sensory differences are a core feature of autism spectrum disorders (ASD) and are predictive of other ASD core symptoms such as social difficulties. However, the neurobiological substrate underlying the functional relationship between sensory and social functioning is poorly understood. Here, we examined whether misregulation of structural plasticity in the somatosensory cortex modulates aberrant social functioning in BTBR mice, a mouse model for autism spectrum disorder-like phenotypes. By locally expressing a dominant-negative form of Cofilin (CofilinS3D; a key regulator of synaptic structure) in the somatosensory cortex, we tested whether somatosensory suppression of Cofilin activity alters social functioning in BTBR mice. Somatosensory Cofilin suppression altered social contact and nest-hide behavior of BTBR mice in a social colony, assessed for seven consecutive days. Subsequent behavioral testing revealed that altered social functioning is related to altered tactile sensory perception; CofilinS3D-treated BTBR mice showed a time-dependent difference in the sensory bedding preference task. These findings show that Cofilin suppression in the somatosensory cortex alters social functioning in BTBR mice and that this is associated with tactile sensory processing, a critical indicator of somatosensory functioning.

PMID:38602737 | PMC:PMC11008688 | DOI:10.1093/cercor/bhae136

Harris J, Loth E, Sethna V.

Front Psychiatry. 2024 Mar 6;15:1331256. doi: 10.3389/fpsyt.2024.1331256. eCollection 2024.

ABSTRACT

Complex trauma is associated with complex-posttraumatic stress disorder (CPTSD). While dissociative processes, developmental factors and systemic factors are implicated in the development of CPTSD, there are no existing systematic reviews examining the underlying pathways linking complex trauma and CPTSD. This study aims to systematically review evidence of mediating factors linking complex trauma exposure in childhood (birth to eighteen years of age) and subsequent development of CPTSD (via self-reports and diagnostic assessments). All clinical, at-risk and community-sampled articles on three online databases (PsycINFO, MedLine and Embase) were systematically searched, along with grey literature from ProQuest. Fifteen articles were eligible for inclusion according to pre-determined eligibility criteria and a search strategy. Five categories of mediating processes were identified: 1) dissociative processes; 2) relationship with self; 3) emotional developmental processes; 4) social developmental processes; and 5) systemic and contextual factors. Further research is required to examine the extent to which targeting these mediators may act as mechanisms for change in supporting individuals to heal from complex trauma.

SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022346152.

PMID:38510809 | PMC:PMC10951104 | DOI:10.3389/fpsyt.2024.1331256

Ward EK, Buitelaar JK, Hunnius S.

Autism Res. 2024 Mar 3. doi: 10.1002/aur.3118. Online ahead of print.

ABSTRACT

Predictive processing accounts of autism posit that autistic individuals’ perception is less biased by expectations than nonautistic individuals’, perhaps through stronger precision-weighting of prediction errors. Since precision-weighting is fundamental to all information processing, under this theory, the differences between autistic and nonautistic individuals should be domain-general and observable in both behavior and brain responses. This study used EEG, behavioral responses, and eye-tracking co-registration during gaze-direction adaptation, to investigate whether increased precision-weighting of prediction errors is evident through smaller adaptation after-effects in autistic adolescents compared with nonautistic peers. Multilevel modeling showed that autistic and nonautistic adolescents’ responses were consistent with behavioral adaptation, with Bayesian statistics providing extremely strong evidence for the absence of a group difference. Cluster-based permutation testing of ERP responses did not show the expected adaptation after-effect but did show habituation to repeated stimulus presentation, and no group difference was detected, a result not consistent with the theoretical account. Combined with the few other available studies, the current findings raise challenges for the theory, suggesting no fundamental difference in precision-weighting of prediction errors in autism.

PMID:38433357 | DOI:10.1002/aur.3118

de Hoyos L, Barendse MT, Schlag F, van Donkelaar MMJ, Verhoef E, Shapland CY, Klassmann A, Buitelaar J, Verhulst B, Fisher SE, Rai D, St Pourcain B.

Nat Commun. 2024 Feb 27;15(1):1770. doi: 10.1038/s41467-024-46128-8.

ABSTRACT

Common genetic variation has been associated with multiple phenotypic features in Autism Spectrum Disorder (ASD). However, our knowledge of shared genetic factor structures contributing to this highly heterogeneous phenotypic spectrum is limited. Here, we developed and implemented a structural equation modelling framework to directly model genomic covariance across core and non-core ASD phenotypes, studying autistic individuals of European descent with a case-only design. We identified three independent genetic factors most strongly linked to language performance, behaviour and developmental motor delay, respectively, studying an autism community sample (N = 5331). The three-factorial structure was largely confirmed in independent ASD-simplex families (N = 1946), although we uncovered, in addition, simplex-specific genetic overlap between behaviour and language phenotypes. Multivariate models across cohorts revealed novel associations, including links between language and early mastering of self-feeding. Thus, the common genetic architecture in ASD is multi-dimensional with overarching genetic factors contributing, in combination with ascertainment-specific patterns, to phenotypic heterogeneity.

PMID:38413609 | PMC:PMC10899248 | DOI:10.1038/s41467-024-46128-8