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Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology.

ABSTRACT: Autism spectrum disorders (ASDs) are complex and heterogeneous developmental disabilities affecting an ever-increasing number of children worldwide. The diverse manifestations and complex, largely genetic aetiology of ASDs pose a major challenge to the identification of unifying neuropathological features. Here we describe the neurodevelopmental defects in mice that carry deleterious alleles of the Wdfy3 gene, recently recognized as causative in ASDs. Loss of Wdfy3 leads to a regionally enlarged cerebral cortex resembling early brain overgrowth described in many children on the autism spectrum. In addition, affected mouse mutants display migration defects of cortical projection neurons, a recognized cause of epilepsy, which is significantly comorbid with autism. Our analysis of affected mouse mutants defines an important role for Wdfy3 in regulating neural progenitor divisions and neural migration in the developing brain. Furthermore, Wdfy3 is essential for cerebral expansion and functional organization while its loss-of-function results in pathological changes characteristic of ASDs.

SUBMITTER: Orosco LA

PROVIDER: S-EPMC4159772 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology.

Orosco Lori A LA Ross Adam P AP Cates Staci L SL Scott Sean E SE Wu Dennis D Sohn Jiho J Pleasure David D Pleasure Samuel J SJ Adamopoulos Iannis E IE Zarbalis Konstantinos S KS

Nature communications 20140908

Autism spectrum disorders (ASDs) are complex and heterogeneous developmental disabilities affecting an ever-increasing number of children worldwide. The diverse manifestations and complex, largely genetic aetiology of ASDs pose a major challenge to the identification of unifying neuropathological features. Here we describe the neurodevelopmental defects in mice that carry deleterious alleles of the Wdfy3 gene, recently recognized as causative in ASDs. Loss of Wdfy3 leads to a regionally enlarged ...[more]

PMID: 25198012

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Project description:Emotional trauma and psychological stress can precipitate cardiac arrhythmia and sudden death through arrhythmogenic effects of efferent sympathetic drive. Patients with preexisting heart disease are particularly at risk. Moreover, generation of proarrhythmic activity patterns within cerebral autonomic centers may be amplified by afferent feedback from a dysfunctional myocardium. An electrocortical potential reflecting afferent cardiac information has been described, reflecting individual differences in interoceptive sensitivity (awareness of one's own heartbeats). To inform our understanding of mechanisms underlying arrhythmogenesis, we extended this approach, identifying electrocortical potentials corresponding to the cortical expression of afferent information about the integrity of myocardial function during stress. We measured changes in cardiac response simultaneously with electroencephalography in patients with established ventricular dysfunction. Experimentally induced mental stress enhanced cardiovascular indices of sympathetic activity (systolic blood pressure, heart rate, ventricular ejection fraction, and skin conductance) across all patients. However, the functional response of the myocardium varied; some patients increased, whereas others decreased, cardiac output during stress. Across patients, heartbeat-evoked potential amplitude at left temporal and lateral frontal electrode locations correlated with stress-induced changes in cardiac output, consistent with an afferent cortical representation of myocardial function during stress. Moreover, the amplitude of the heartbeat-evoked potential in the left temporal region reflected the proarrhythmic status of the heart (inhomogeneity of left ventricular repolarization). These observations delineate a cortical representation of cardiac function predictive of proarrhythmic abnormalities in cardiac repolarization. Our findings highlight the dynamic interaction of heart and brain in stress-induced cardiovascular morbidity.

Project description:BackgroundNeurocognitive investigations suggest that conscious sensory perception depends on recurrent neuronal interactions among sensory, parietal, and frontal cortical regions, which are suppressed by general anesthetics. The purpose of this work was to investigate if local interactions in sensory cortex are also altered by anesthetics. The authors hypothesized that desflurane would reduce recurrent neuronal interactions in cortical layer-specific manner consistent with the anatomical disposition of feedforward and feedback pathways.MethodsSingle-unit neuronal activity was measured in freely moving adult male rats (268 units; 10 animals) using microelectrode arrays chronically implanted in primary and secondary visual cortex. Layer-specific directional interactions were estimated by mutual information and transfer entropy of multineuron spike patterns within and between cortical layers three and five. The effect of incrementally increasing and decreasing steady-state concentrations of desflurane (0 to 8% to 0%) was tested for statistically significant quadratic trend across the successive anesthetic states.ResultsDesflurane produced robust, state-dependent reduction (P = 0.001) of neuronal interactions between primary and secondary visual areas and between layers three and five, as indicated by mutual information (37 and 41% decrease at 8% desflurane from wakeful baseline at [mean ± SD] 0.52 ± 0.51 and 0.53 ± 0.51 a.u., respectively) and transfer entropy (77 and 78% decrease at 8% desflurane from wakeful baseline at 1.86 ± 1.56 a.u. and 1.87 ± 1.67 a.u., respectively). In addition, a preferential suppression of feedback between secondary and primary visual cortex was suggested by the reduction of directional index of transfer entropy overall (P = 0.001; 89% decrease at 8% desflurane from 0.11 ± 0.18 a.u. at baseline) and specifically, in layer five (P = 0.001; 108% decrease at 8% desflurane from 0.12 ± 0.19 a.u. at baseline).ConclusionsDesflurane anesthesia reduces neuronal interactions in visual cortex with a preferential effect on feedback. The findings suggest that neuronal disconnection occurs locally, among hierarchical sensory regions, which may contribute to global functional disconnection underlying anesthetic-induced unconsciousness.

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Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology.

Publications

Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology.

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