Dataset Information

Layer-specific gene expression in epileptogenic type II focal cortical dysplasia: normal-looking neurons reveal the presence of a hidden laminar organization.

ABSTRACT:

Background

Type II focal cortical dysplasias (FCDs) are malformations of cortical development characterised by the disorganisation of the normal neocortical structure and the presence of dysmorphic neurons (DNs) and balloon cells (BCs). The pathogenesis of FCDs has not yet been clearly established, although a number of histopathological patterns and molecular findings suggest that they may be due to abnormal neuronal and glial proliferation and migration processes.In order to gain further insights into cortical layering disruption and investigate the origin of DNs and BCs, we used in situ RNA hybridisation of human surgical specimens with a neuropathologically definite diagnosis of Type IIa/b FCD and a panel of layer-specific genes (LSGs) whose expression covers all cortical layers. We also used anti-phospho-S6 ribosomal protein antibody to investigate mTOR pathway hyperactivation.

Results

LSGs were expressed in both normal and abnormal cells (BCs and DNs) but their distribution was different. Normal-looking neurons, which were visibly reduced in the core of the lesion, were apparently located in the appropriate cortical laminae thus indicating a partial laminar organisation. On the contrary, DNs and BCs, labelled with anti-phospho-S6 ribosomal protein antibody, were spread throughout the cortex without any apparent rule and showed a highly variable LSG expression pattern. Moreover, LSGs did not reveal any differences between Type IIa and IIb FCD.

Conclusion

These findings suggest the existence of hidden cortical lamination involving normal-looking neurons, which retain their ability to migrate correctly in the cortex, unlike DNs which, in addition to their morphological abnormalities and mTOR hyperactivation, show an altered migratory pattern.Taken together these data suggest that an external or environmental hit affecting selected precursor cells during the very early stages of cortical development may disrupt normal cortical development.

SUBMITTER: Rossini L

PROVIDER: S-EPMC4023625 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Publications

Layer-specific gene expression in epileptogenic type II focal cortical dysplasia: normal-looking neurons reveal the presence of a hidden laminar organization.

Rossini Laura L Medici Valentina V Tassi Laura L Cardinale Francesco F Tringali Giovanni G Bramerio Manuela M Villani Flavio F Spreafico Roberto R Garbelli Rita R

Acta neuropathologica communications 20140415

<h4>Background</h4>Type II focal cortical dysplasias (FCDs) are malformations of cortical development characterised by the disorganisation of the normal neocortical structure and the presence of dysmorphic neurons (DNs) and balloon cells (BCs). The pathogenesis of FCDs has not yet been clearly established, although a number of histopathological patterns and molecular findings suggest that they may be due to abnormal neuronal and glial proliferation and migration processes.In order to gain furthe ...[more]

PMID: 24735483

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Project description:Focal cortical dysplasias are a common subtype of malformation of cortical development, which frequently presents with a spectrum of cognitive and behavioural abnormalities as well as pharmacoresistant epilepsy. Focal cortical dysplasia type II is typically caused by somatic mutations resulting in mammalian target of rapamycin (mTOR) hyperactivity, and is the commonest pathology found in children undergoing epilepsy surgery. However, surgical resection does not always result in seizure freedom, and is often precluded by proximity to eloquent brain regions. Gene therapy is a promising potential alternative treatment and may be appropriate in cases that represent an unacceptable surgical risk. Here, we evaluated a gene therapy based on overexpression of the Kv1.1 potassium channel in a mouse model of frontal lobe focal cortical dysplasia. An engineered potassium channel (EKC) transgene was placed under control of a human promoter that biases expression towards principal neurons (CAMK2A) and packaged in an adeno-associated viral vector (AAV9). We used an established focal cortical dysplasia model generated by in utero electroporation of frontal lobe neural progenitors with a constitutively active human Ras homolog enriched in brain (RHEB) plasmid, an activator of mTOR complex 1. We characterized the model by quantifying electrocorticographic and behavioural abnormalities, both in mice developing spontaneous generalized seizures and in mice only exhibiting interictal discharges. Injection of AAV9-CAMK2A-EKC in the dysplastic region resulted in a robust decrease (∼64%) in the frequency of seizures. Despite the robust anti-epileptic effect of the treatment, there was neither an improvement nor a worsening of performance in behavioural tests sensitive to frontal lobe function. AAV9-CAMK2A-EKC had no effect on interictal discharges or behaviour in mice without generalized seizures. AAV9-CAMK2A-EKC gene therapy is a promising therapy with translational potential to treat the epileptic phenotype of mTOR-related malformations of cortical development. Cognitive and behavioural co-morbidities may, however, resist an intervention aimed at reducing circuit excitability.

Project description:Neuroimaging studies have consistently shown distributed brain anomalies in epilepsy syndromes associated with a focal structural lesion, particularly mesiotemporal sclerosis. Conversely, a system-level approach to focal cortical dysplasia has been rarely considered, likely due to methodological difficulties in addressing variable location and topography. Given the known heterogeneity in focal cortical dysplasia histopathology, we hypothesized that lesional connectivity consists of subtypes with distinct structural signatures. Furthermore, in light of mounting evidence for focal anomalies impacting whole-brain systems, we postulated that patterns of focal cortical dysplasia connectivity may exert differential downstream effects on global network topology. We studied a cohort of patients with histologically verified focal cortical dysplasia type II (n = 27), and age- and sex-matched healthy controls (n = 34). We subdivided each lesion into similarly sized parcels and computed their connectivity to large-scale canonical functional networks (or communities). We then dichotomized connectivity profiles of lesional parcels into those belonging to the same functional community as the focal cortical dysplasia (intra-community) and those adhering to other communities (inter-community). Applying hierarchical clustering to community-reconfigured connectome profiles identified three lesional classes with distinct patterns of functional connectivity: decreased intra- and inter-community connectivity, a selective decrease in intra-community connectivity, and increased intra- as well as inter-community connectivity. Hypo-connectivity classes were mainly composed of focal cortical dysplasia type IIB, while the hyperconnected lesions were type IIA. With respect to whole-brain networks, patients with hypoconnected focal cortical dysplasia and marked structural damage showed only mild imbalances, while those with hyperconnected subtle lesions had more pronounced topological alterations. Correcting for interictal epileptic discharges did not impact connectivity patterns. Multivariate structural equation analysis provided a mechanistic model of such complex, diverging interactions, whereby the focal cortical dysplasia structural makeup shapes its functional connectivity, which in turn modulates whole-brain network topology.

Dataset Information

Layer-specific gene expression in epileptogenic type II focal cortical dysplasia: normal-looking neurons reveal the presence of a hidden laminar organization.

Background

Results

Conclusion

Publications

Layer-specific gene expression in epileptogenic type II focal cortical dysplasia: normal-looking neurons reveal the presence of a hidden laminar organization.

Similar Datasets

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