Agenesis of the corpus callosum: genetic, developmental and functional aspects of connectivity. Nat Rev Neurosci 8:287-299

California Institute of Technology, MC 228-77 Pasadena, California 91125, USA.
Nature reviews Neuroscience (Impact Factor: 31.43). 05/2007; 8(4):287-99. DOI: 10.1038/nrn2107
Source: PubMed


Agenesis of the corpus callosum (AgCC), a failure to develop the large bundle of fibres that connect the cerebral hemispheres, occurs in 1:4000 individuals. Genetics, animal models and detailed structural neuroimaging are now providing insights into the developmental and molecular bases of AgCC. Studies using neuropsychological, electroencephalogram and functional MRI approaches are examining the resulting impairments in emotional and social functioning, and have begun to explore the functional neuroanatomy underlying impaired higher-order cognition. The study of AgCC could provide insight into the integrated cerebral functioning of healthy brains, and may offer a model for understanding certain psychiatric illnesses, such as schizophrenia and autism.

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    • "Among them, the Disrupted-in-Schizophrenia 1 (DISC1) gene, named because of its possible role in schizophrenia and related disorders (Millar et al., 2000), was found to be highly expressed in the developing CC of embryonic mice. Osbun and colleagues (2011) also identified a variant form of the DISC1 gene, possibly pathogenic, in 144 AgCC patients, further suggesting an important role of this gene in the development of the CC and in the etiology of AgCC (Osbun et al., 2011; Paul et al., 2007). Since AgCC is an heterogeneous condition, symptoms can vary greatly between affected individuals, ranging from relative absence to severe impairment requiring special education and assistance in every day living (Paul et al., 2004; Siffredi et al., 2013). "
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    ABSTRACT: Agenesis of the corpus callosum (AgCC) is a congenital malformation that can occur in isolation or in association with other neurological conditions. Although the behavioral manifestations associated with AgCC have been widely studied, the effects of complete absence of the corpus callosum (CC) on cerebral cortex anatomy are still not completely understood. In this study, cortical thickness in adults with complete AgCC was compared to a group of healthy controls. Results showed highly variable patterns of cortical thickness in AgCC individuals, with few areas showing significant and consistent alterations including primary visual cortex, primary somatosensory cortex and primary motor cortex. These results suggest relatively limited effects of AgCC on cortical morphology, which are mostly restricted to primary sensory and motor areas.
    Neuropsychologia 09/2015; 77. DOI:10.1016/j.neuropsychologia.2015.09.020 · 3.30 Impact Factor
    • "In a critical experiment, we than tested in a second approach, whether this contralaterally induced iM1 suppression is absent in patients with AgCC. AgCC is a rare condition, in which callosal fibers are congenitally completely or partially absent, caused by different genetic or environmental factors during prenatal callosal development [15]. As a consequence AgCC patients usually show prolonged visual interhemispheric transfer times [16] [17] and deficiencies in different higher cognitive abilities, where interhemispheric integration is important [18] [19]. "
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    ABSTRACT: During unilateral hand movements the activity of the contralateral primary motor cortex (cM1) is increased while the activity of the ipsilateral M1 (iM1) is decreased. A potential explanation for this asymmetric activity pattern is transcallosal cM1-to-iM1 inhibitory control. To test this hypothesis, we examined interhemispheric motor inhibition in acallosal patients. We measured fMRI activity in iM1 and cM1 in acallosal patients during unilateral hand movements and compared their motor activity pattern to that of healthy controls. In controls, fMRI activation in cM1 was significantly higher than in iM1, reflecting a normal differential task-related M1 activity. Additional functional connectivity analysis revealed that iM1 activity was strongly suppressed by cM1. Furthermore, DTI analysis indicated that this contralaterally induced suppression was mediated by microstructural properties of specific callosal fibers interconnecting both M1s. In contrast, acallosal patients did not show a clear differential activity pattern between cM1 and iM1. The more symmetric pattern was due to an elevated task-related iM1 activity in acallosal patients, which was significantly higher than iM1 activity in a subgroup of gender and age-matched controls. Also, interhemispheric motor suppression was completely absent in acallosal patients. These findings suggest that absence of callosal connections reduces inhibitory interhemispheric motor interactions between left and right M1. This effect may reveal novel aspects of mechanisms in communication of two hemispheres and establishment of brain asymmetries in general. Copyright © 2015. Published by Elsevier B.V.
    Behavioural brain research 07/2015; 293. DOI:10.1016/j.bbr.2015.07.016 · 3.03 Impact Factor
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    • "Perturbations in proliferation of these neural progenitors affect the timing and generation of cortical projection neurons, resulting in aberrant cortical circuitry and connectivity. Indeed, abnormalities associated with aberrant numbers of upper layer CPNs are associated with defects in abstract reasoning, problem solving and generalization (Paul et al., 2007) and have been reported in patients with ASDs (Minshew and Williams, 2007; Freitag et al., 2009). The new murine model of autism in which the chromosomal region syngenic to human 16p11.2 "
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    ABSTRACT: Autism spectrum disorders are complex, highly heritable neurodevelopmental disorders affecting ∼1 in 100 children. Copy number variations of human chromosomal region 16p11.2 are genetically linked to 1% of autism-related disorders. This interval contains the MAPK3 gene, which encodes the MAP kinase, ERK1. Mutations in upstream elements regulating the ERK pathway are genetically linked to autism and other disorders of cognition including the neuro-cardio-facial cutaneous syndromes and copy number variations. We report that a murine model of human 16p11.2 deletion exhibits a reduction in brain size and perturbations in cortical cytoarchitecture. We observed enhanced progenitor proliferation and premature cell cycle exit, which are a consequence of altered levels of downstream ERK effectors cyclin D1 and p27(Kip1) during mid-neurogenesis. The increased progenitor proliferation and cell cycle withdrawal resulted in premature depletion of progenitor pools, altering the number and frequency of neurons ultimately populating cortical lamina. Specifically, we found a reduced number of upper layer pyramidal neurons and an increase in layer VI corticothalamic projection neurons, reflecting the altered cortical progenitor proliferation dynamics in these mice. Importantly, we observed a paradoxical increase in ERK signaling in mid-neurogenesis in the 16p11.2del mice, which is coincident with the development of aberrant cortical cytoarchitecture. The 16p11.2del mice exhibit anxiety-like behaviors and impaired memory. Our findings provide evidence of ERK dysregulation, developmental abnormalities in neurogenesis, and behavioral impairment associated with the 16p11.2 chromosomal deletion. Copyright © 2015 the authors 0270-6474/15/353190-11$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2015; 35(7):3190-200. DOI:10.1523/JNEUROSCI.4864-13.2015 · 6.34 Impact Factor
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