scholarly journals A giant ankyrin-B mechanism for neuro-diversity/divergence through stochastic ectopic axon projections

2018 ◽  
Author(s):  
Rui Yang ◽  
Kathryn K. Walder-Christensen ◽  
Namsoo Kim ◽  
Danwei Wu ◽  
Damaris Lorenzo ◽  
...  
Keyword(s):  
Brain Connectivity ◽  
Structural Connectivity ◽  
Autism Spectrum ◽  
Membrane Domains ◽  
Social Deficits ◽  
Loss Of Function ◽  
High Confidence ◽  
Microtubule Stabilization ◽  
Wide Range ◽  
Ankyrin B

ABSTRACTANK2 is a high-confidence autism spectrum disorder (ASD) gene where affected individuals exhibit diverse symptoms with a wide range of IQ. We report a cellular mechanism resulting in stochastic brain connectivity that provides a rationale for both gain and loss of function due to ANK2 mutation. Deficiency of giant ankyrin-B (ankB), the neurospecific ANK2 mutation target, results in ectopic CNS axon tracts associated with increased axonal branching. We elucidate a mechanism limiting axon branching, whereby giant ankB is recruited by L1CAM to periodic axonal plasma membrane domains where it coordinates cortical microtubules and prevents microtubule stabilization of nascent axon branches. Heterozygous giant ankB mutant mice exhibit innate social deficits combined with normal/enhanced cognitive function. Thus, giant ankB-deficiency results in gain of aberrant structural connectivity with penetrant behavioral consequences that may contribute to both high and low-function ASD and other forms of neurodiversity/divergence.

scholarly journals ANK2 autism mutation targeting giant ankyrin-B promotes axon branching and ectopic connectivity

2019 ◽  
Vol 116 (30) ◽  
pp. 15262-15271 ◽  
Author(s):  
Rui Yang ◽  
Kathryn K. Walder-Christensen ◽  
Namsoo Kim ◽  
Danwei Wu ◽  
Damaris N. Lorenzo ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Structural Connectivity ◽  
Autism Spectrum ◽  
Excitatory Synapses ◽  
Membrane Domains ◽  
Axon Branching ◽  
Alternatively Spliced ◽  
Spliced Variant ◽  
Ankyrin B ◽  
L1 Cell Adhesion Molecule

Giant ankyrin-B (ankB) is a neurospecific alternatively spliced variant of ANK2, a high-confidence autism spectrum disorder (ASD) gene. We report that a mouse model for human ASD mutation of giant ankB exhibits increased axonal branching in cultured neurons with ectopic CNS axon connectivity, as well as with a transient increase in excitatory synapses during postnatal development. We elucidate a mechanism normally limiting axon branching, whereby giant ankB localizes to periodic axonal plasma membrane domains through L1 cell-adhesion molecule protein, where it couples microtubules to the plasma membrane and prevents microtubule entry into nascent axon branches. Giant ankB mutation or deficiency results in a dominantly inherited impairment in selected communicative and social behaviors combined with superior executive function. Thus, gain of axon branching due to giant ankB-deficiency/mutation is a candidate cellular mechanism to explain aberrant structural connectivity and penetrant behavioral consequences in mice as well as humans bearing ASD-related ANK2 mutations.

scholarly journals Unique mapping of structural and functional connectivity on cognition

2018 ◽  
Author(s):  
J. Zimmermann ◽  
J.G. Griffiths ◽  
A.R. McIntosh
Keyword(s):  
Functional Connectivity ◽  
Brain Connectivity ◽  
Structural Connectivity ◽  
Brain Regions ◽  
Unique Mapping ◽  
Human Connectome Project ◽  
Behavioural Patterns ◽  
Wide Range ◽  
Psychological Tasks ◽  
New Evidence

AbstractThe unique mapping of structural and functional brain connectivity (SC, FC) on cognition is currently not well understood. It is not clear whether cognition is mapped via a global connectome pattern or instead is underpinned by several sets of distributed connectivity patterns. Moreover, we also do not know whether the pattern of SC and of FC that underlie cognition are overlapping or distinct. Here, we study the relationship between SC and FC and an array of psychological tasks in 609 subjects from the Human Connectome Project (HCP). We identified several sets of connections that each uniquely map onto different aspects of cognitive function. We found a small number of distributed SC and a larger set of cortico-cortical and cortico-subcortical FC that express this association. Importantly, SC and FC each show unique and distinct patterns of variance across subjects and differential relationships to cognition. The results suggest that a complete understanding of connectome underpinnings of cognition calls for a combination of the two modalities.Significance StatementStructural connectivity (SC), the physical white-matter inter-regional pathways in the brain, and functional connectivity (FC), the temporal co-activations between activity of brain regions, have each been studied extensively. Little is known, however, about the distribution of variance in connections as they relate to cognition. Here, in a large sample of subjects (N = 609), we showed that two sets of brain-behavioural patterns capture the correlations between SC, and FC with a wide range of cognitive tasks, respectively. These brain-behavioural patterns reveal distinct sets of connections within the SC and the FC network and provide new evidence that SC and FC each provide unique information for cognition.

scholarly journals Giant ankyrin-B mediates transduction of axon guidance and collateral branch pruning factor sema 3A

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Blake A Creighton ◽  
Simone Afriyie ◽  
Deepa Ajit ◽  
Cristine R Casingal ◽  
Kayleigh M Voos ◽  
...  
Keyword(s):  
Brain Connectivity ◽  
Autism Spectrum ◽  
Axon Collateral ◽  
Collateral Branch ◽  
Cellular Assays ◽  
Behavioral Abnormalities ◽  
Neuropilin 1 ◽  
Branch Formation ◽  
Ankyrin B

Variants in the high confident autism spectrum disorder (ASD) gene ANK2 target both ubiquitously expressed 220 kDa ankyrin-B and neurospecific 440 kDa ankyrin-B (AnkB440) isoforms. Previous work showed that knock-in mice expressing an ASD-linked Ank2 variant yielding a truncated AnkB440 product exhibit ectopic brain connectivity and behavioral abnormalities. Expression of this variant or loss of AnkB440 caused axonal hyperbranching in vitro, which implicated AnkB440 microtubule bundling activity in suppressing collateral branch formation. Leveraging multiple mouse models, cellular assays, and live microscopy, we show that AnkB440 also modulates axon collateral branching stochastically by reducing the number of F-actin-rich branch initiation points. Additionally, we show that AnkB440 enables growth cone (GC) collapse in response to chemorepellent factor semaphorin 3 A (Sema 3 A) by stabilizing its receptor complex L1 cell adhesion molecule/neuropilin-1. ASD-linked ANK2 variants failed to rescue Sema 3A-induced GC collapse. We propose that impaired response to repellent cues due to AnkB440 deficits leads to axonal targeting and branch pruning defects and may contribute to the pathogenicity of ANK2 variants.

scholarly journals Structurally constrained effective brain connectivity

2021 ◽  
Author(s):  
Alessandro Crimi
Keyword(s):  
Community Detection ◽  
Autoregressive Model ◽  
Brain Connectivity ◽  
Effective Connectivity ◽  
Structural Connectivity ◽  
Ground Truth ◽  
Autism Spectrum ◽  
Case Control ◽  
Functional Dependencies ◽  
The Brain

The relationship between structure and function is of interest in many research fields involving the study of complex biological processes. In neuroscience in particular, the fusion of structural and functional data can help to understand the underlying principles of the operational networks in the brain. To address this issue, this paper proposes a constrained autoregressive model leading to a representation of effective connectivity that can be used to better understand how the structure modulates the function. Or simply, it can be used to find novel biomarkers characterizing groups of subjects. In practice, an initial structural connectivity representation is re-weighted to explain the functional co-activations. This is obtained by minimizing the reconstruction error of an autoregressive model constrained by the structural connectivity prior. The model has been designed to also include indirect connections, allowing to split direct and indirect components in the functional connectivity, and it can be used with raw and deconvoluted BOLD signal.The derived representation of dependencies was compared to the well known dynamic causal model, giving results closer to known ground-truth. Further evaluation of the proposed effective network was performed on two typical tasks. In a first experiment the direct functional dependencies were tested on a community detection problem, where the brain was partitioned using the effective networks across multiple subjects. In a second experiment the model was validated in a case-control task, which aimed at differentiating healthy subjects from individuals with autism spectrum disorder. Results showed that using effective connectivity leads to clusters better describing the functional interactions in the community detection task, while maintaining the original structural organization, and obtaining a better discrimination in the case-control classification task.

scholarly journals Giant ankyrin-B mediates transduction of axon guidance and collateral branch pruning factor Sema 3A

2021 ◽  
Author(s):  
Damaris N Lorenzo ◽  
Blake A Creighton ◽  
Deepa Ajit ◽  
Simone Afriyie ◽  
Julia C Bay
Keyword(s):  
Brain Connectivity ◽  
Autism Spectrum ◽  
Axonal Guidance ◽  
Axon Collateral ◽  
Collateral Branch ◽  
Behavioral Abnormalities ◽  
Neuropilin 1 ◽  
Branch Formation ◽  
Ankyrin B

Variants in the high confident autism spectrum disorder gene ANK2 target both ubiquitously expressed 220-kDa ankyrin- B and neurospecific 440-kDa ankyrin-B (AnkB440) isoforms. Previous work showed that knock-in mice expressing an ASD linked Ank2 variant yielding a truncated AnkB440 product exhibit ectopic brain connectivity and behavioral abnormalities. Expression of this variant or loss of AnkB440 caused axonal hyperbranching in vitro, which implicated AnkB440 microtubule bundling activity in suppressing collateral branch formation. Leveraging multiple mouse models, cellular assays, and live microscopy, we show that AnkB440 also modulates axon collateral branching stochastically by reducing the number of F-actin-rich branch initiation points. Additionally, we show that AnkB440 enables growth cone (GC) collapse in response to chemorepellent factor semaphorin 3A (Sema 3A) by stabilizing its receptor complex L1 cell adhesion molecule/neuropilin-1. ASD-linked ANK2 variants failed to rescue Sema 3A-induced GC collapse. We propose that impaired response to repellent cues due to AnkB440 deficits leads to axonal guidance and branch pruning defects and may contribute to the pathogenicity of ANK2 variants.

scholarly journals Wnt/β-Catenin-Dependent Transcription in Autism Spectrum Disorders

2021 ◽  
Vol 14 ◽  
Author(s):  
Mario O. Caracci ◽  
Miguel E. Avila ◽  
Francisca A. Espinoza-Cavieres ◽  
Héctor R. López ◽  
Giorgia D. Ugarte ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Cell Fate ◽  
Pyramidal Neurons ◽  
Cell Types ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
High Confidence ◽  
Developmental Abnormalities ◽  
Cell Fate Decisions ◽  
Spectrum Disorders

Autism spectrum disorders (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by synaptic dysfunction and defects in dendritic spine morphology. In the past decade, an extensive list of genes associated with ASD has been identified by genome-wide sequencing initiatives. Several of these genes functionally converge in the regulation of the Wnt/β-catenin signaling pathway, a conserved cascade essential for stem cell pluripotency and cell fate decisions during development. Here, we review current information regarding the transcriptional program of Wnt/β-catenin signaling in ASD. First, we discuss that Wnt/β-catenin gain and loss of function studies recapitulate brain developmental abnormalities associated with ASD. Second, transcriptomic approaches using patient-derived induced pluripotent stem cells (iPSC) cells, featuring mutations in high confidence ASD genes, reveal a significant dysregulation in the expression of Wnt signaling components. Finally, we focus on the activity of chromatin-remodeling proteins and transcription factors considered high confidence ASD genes, including CHD8, ARID1B, ADNP, and TBR1, that regulate Wnt/β-catenin-dependent transcriptional activity in multiple cell types, including pyramidal neurons, interneurons and oligodendrocytes, cells which are becoming increasingly relevant in the study of ASD. We conclude that the level of Wnt/β-catenin signaling activation could explain the high phenotypical heterogeneity of ASD and be instrumental in the development of new diagnostics tools and therapies.

scholarly journals Homozygous loss of autism-risk geneCNTNAP2results in reduced local and long-range prefrontal functional connectivity

2016 ◽  
Author(s):  
Adam Liska ◽  
Alice Bertero ◽  
Ryszard Gomolka ◽  
Mara Sabbioni ◽  
Alberto Galbusera ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
Long Range ◽  
Brain Connectivity ◽  
Resting State Fmri ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Functional Impairments ◽  
Social Investigation ◽  
Reduced Frequency ◽  
Cortical Regions

AbstractFunctional connectivity aberrancies, as measured with resting-state fMRI (rsfMRI), have been consistently observed in the brain of autism spectrum disorders (ASD) patients. However, the genetic and neurobiological underpinnings of these findings remain unclear. Homozygous mutations in Contactin Associated Protein-like 2 (CNTNAP2), a neurexin-related cell-adhesion protein, are strongly linked to autism and epilepsy. Here we used rsfMRI to show that homozygous mice lackingCntnap2exhibit reduced long-range and local functional connectivity in prefrontal and midline brain “connectivity hubs”. Long-range rsfMRI connectivity impairments affected heteromodal cortical regions and were prominent between fronto-posterior components of the mouse default-mode network (DMN), an effect that was associated with reduced social investigation, a core “autism trait” in mice. Notably, viral tracing revealed reduced frequency of prefrontal-projecting neural clusters in the cingulate cortex ofCntnap2−/−mutants, suggesting a possible contribution of defective mesoscale axonal wiring to the observed functional impairments. Macroscale cortico-cortical white matter organization appeared to be otherwise preserved in these animals. These findings reveal a key contribution of ASD-associated gene CNTNAP2 in modulating macroscale functional connectivity, and suggest that homozygous loss-of-function mutations in this gene may predispose to neurodevelopmental disorders and autism through a selective dysregulation of connectivity in integrative prefrontal areas.

scholarly journals Structurally Constrained Effective Brain Connectivity

2018 ◽  
Author(s):  
Alessandro Crimi ◽  
Luca Dodero ◽  
Fabio Sambataro ◽  
Vittorio Murino ◽  
Diego Sona
Keyword(s):  
Autoregressive Model ◽  
Brain Research ◽  
Brain Connectivity ◽  
Effective Connectivity ◽  
Structural Connectivity ◽  
Young Patients ◽  
Autism Spectrum ◽  
Case Control ◽  
Brain Targeting ◽  
The Brain

How function arises from structure is of interest in many fields from proteomics to neuroscience. In particular, among the brain research community the fusion of structure and function data can shed new lights on underlying operational network principles in the brain. Targeting this issue, the manuscript proposes a constrained autoregressive model generating “effective” connectivity given structural and functional information. In practice, an initial structural connectivity representation is altered according to functional data, by minimizing the reconstruction error of an autoregressive model constrained by the structural prior. The proposed model has been tested in a community detection framework, where the brain is partitioned using the effective networks across multiple subjects. The model is further validated in a case-control experiment, which aims at differentiating healthy subjects from young patients affected by autism spectrum disorder. Results showed that using effective connectivity resulted in clusters that better describe the functional interactions between different regions while maintaining the structural organization, and a better discrimination in the case-control classification task.

scholarly journals Network Curvature as a Hallmark of Brain Structural Connectivity

2017 ◽  
Author(s):  
Hamza Farooq ◽  
Yongxin Chen ◽  
Tryphon T. Georgiou ◽  
Allen Tannenbaum ◽  
Christophe Lenglet
Keyword(s):  
Ricci Curvature ◽  
Biological Networks ◽  
Brain Connectivity ◽  
Brain Networks ◽  
Structural Connectivity ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Or Efficiency ◽  
Healthy Development ◽  
Structural Networks

AbstractStudies show that while brain networks are remarkably robust to a variety of adverse events, such as injuries and lesions due to accidents or disease, they may be fragile when the disturbance takes place in specific locations. This seems to be the case for diseases in which accumulated changes in network topology dramatically affect certain sensitive areas. To this end, previous attempts have been made to quantify robustness and fragility of brain functionality in two broadly defined ways: (i) utilizing model-based techniques to predict lesion effects, and (ii) studying empirical effects from brain lesions due to injury or disease. Both directions aim at assessing functional connectivity changes resulting from structural network variations. In the present work, we follow a more geometric viewpoint that is based on a notion of curvature of networks, the so-called Ollivier-Ricci curvature. A similar approach has been used in recent studies to quantify financial market robustness as well as to differentiate biological networks corresponding to cancer cells from normal cells. The same notion of curvature, defined at the node level for brain networks obtained from MRI data, may help identify and characterize the effects of diseases on specific brain regions. In the present paper, we apply the Ollivier-Ricci curvature to brain structural networks to: i) Demonstrate its unique ability to identify robust (or fragile) brain regions in healthy subjects. We compare our results to previously published work which identified a unique set of regions (called structural core) of the human cerebral cortex. This novel characterization of brain networks, complementary to measures such as degree, strength, clustering or efficiency, may be particularly useful to detect and monitor candidate areas for targeting by surgery (e.g. deep brain stimulation) or pharmaco-therapeutic agents; ii) Illustrate the power our curvature-derived measures to track changes in brain connectivity with healthy development/aging and; iii) Detect changes in brain structural connectivity in people with Autism Spectrum Disorders (ASD) which are in agreement with previous morphometric MRI studies.

scholarly journals Network curvature as a hallmark of brain structural connectivity

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Hamza Farooq ◽  
Yongxin Chen ◽  
Tryphon T. Georgiou ◽  
Allen Tannenbaum ◽  
Christophe Lenglet
Keyword(s):  
Financial Market ◽  
Biological Networks ◽  
Healthy Subjects ◽  
Structural Changes ◽  
Brain Connectivity ◽  
Empirical Studies ◽  
Structural Connectivity ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Structural Networks

Abstract Although brain functionality is often remarkably robust to lesions and other insults, it may be fragile when these take place in specific locations. Previous attempts to quantify robustness and fragility sought to understand how the functional connectivity of brain networks is affected by structural changes, using either model-based predictions or empirical studies of the effects of lesions. We advance a geometric viewpoint relying on a notion of network curvature, the so-called Ollivier-Ricci curvature. This approach has been proposed to assess financial market robustness and to differentiate biological networks of cancer cells from healthy ones. Here, we apply curvature-based measures to brain structural networks to identify robust and fragile brain regions in healthy subjects. We show that curvature can also be used to track changes in brain connectivity related to age and autism spectrum disorder (ASD), and we obtain results that are in agreement with previous MRI studies.

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