New insights into a spectrum of developmental malformations related to mTOR dysregulations: challenges and perspectives.

In recent years the role of the mammalian target of rapamycin (mTOR) pathway has emerged as crucial for normal cortical development. Therefore, it is not surprising that aberrant activation of mTOR is associated with developmental malformations and epileptogenesis. A broad spectrum of malformations of cortical development, such as focal cortical dysplasia (FCD) and tuberous sclerosis complex (TSC), have been linked to either germline or somatic mutations in mTOR pathway-related genes, commonly summarised under the umbrella term 'mTORopathies'. However, there are still a number of unanswered questions regarding the involvement of mTOR in the pathophysiology of these abnormalities. Therefore, a monogenetic disease, such as TSC, can be more easily applied as a model to study the mechanisms of epileptogenesis and identify potential new targets of therapy. Developmental neuropathology and genetics demonstrate that FCD IIb and hemimegalencephaly are the same diseases. Constitutive activation of mTOR signalling represents a shared pathogenic mechanism in a group of developmental malformations that have histopathological and clinical features in common, such as epilepsy, autism and other comorbidities. We seek to understand the effect of mTOR dysregulation in a developing cortex with the propensity to generate seizures as well as the aftermath of the surrounding environment, including the white matter.

Altered gene expression in the dorsolateral prefrontal cortex of individuals with schizophrenia.

The underlying pathology of schizophrenia (SZ) is likely as heterogeneous as its symptomatology. A variety of cortical and subcortical regions, including the prefrontal cortex, have been implicated in its pathology, and a number of genes have been identified as risk factors for disease development. We used in situ hybridization (ISH) to examine the expression of 58 genes in the dorsolateral prefrontal cortex (DLPFC, comprised of Brodmann areas 9 and 46) from 19 individuals with a premorbid diagnosis of SZ and 33 control individuals. Genes were selected based on: (1) previous identification as risk factors for SZ; (2) cell type markers or (3) laminar markers. Cell density and staining intensity were compared in the DLPFC, as well as separately in Brodmann areas 9 and 46. The expression patterns of a variety of genes, many of which are associated with the GABAergic system, were altered in SZ when compared with controls. Additional genes, including C8orf79 and NR4A2, showed alterations in cell density or staining intensity between the groups, highlighting the need for additional studies. Alterations were, with only a few exceptions, limited to Brodmann area 9, suggesting regional specificity of pathology in the DLPFC. Our results agree with previous studies on the GABAergic involvement in SZ, and suggest that areas 9 and 46 may be differentially affected in the disease. This study also highlights additional genes that may be altered in SZ, and indicates that these potentially interesting genes can be identified by ISH and high-throughput image analysis techniques.

Tau epitope display in progressive supranuclear palsy and corticobasal degeneration.

Filamentous aggregates of the protein tau are a prominent feature of Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). However, the extent to which the molecular structure of the tau in these aggregates is similar or differs between these diseases is unclear. We approached this question by examining these disorders with a panel of antibodies that represent different structural, conformational, and cleavage-specific tau epitopes. Although each of these antibodies reveals AD pathology, they resolved into three classes with respect to PSP and CBD: AD2 and Tau-46.1 stained the most tau pathology in all cases; Tau-1, 2, 5, and 12 exhibited variable reactivity; and Tau-66 and MN423 did not reveal any tau pathology. In addition, hippocampal neurofibrillary tangles in these cases showed a predominantly PSP/CBD-like, rather than AD-like, staining pattern. These results indicate that the patterns of the tau epitopes represented by this panel that reside in the pathological aggregates of PSP and CBD are similar to each other but distinct from that of AD.