Characteristics of cortical tubers in tuberous sclerosis

Туберозный склероз - орфанное аутосомно-доминантное наследственное заболевание, причиной которого являются инактивирующие мутации в генах TSC1 или TSC2, сопровождающиеся гиперактивацией сигнального пути mTOR, отвечающего за регуляцию роста, пролиферации, выживаемости клеток, а также аутофагии. Одним из основных клинических симптомов туберозного склероза является наличие туберов в головном мозге. Данные образования характеризуются нарушениями кортикальной ламинации, появлением аномальных нейронов и выраженным глиозом. Известно, что количество кортикальных туберов коррелирует с развитием нейропсихиатрических расстройств, в том числе фармакорезистентной эпилепсии. В данной статье освещены вопросы молекулярной генетики туберозного склероза, приведена гистопатологическая характеристика кортикальных туберов, рассмотрен молекулярный механизм морфогенеза кортикальных туберов, а также приведены данные о связи этих образований с развитием неврологических проявлений и методах их лечения. Tuberous sclerosis is an orphan autosomal dominant hereditary disease caused by inactivating mutations in the TSC1 or TSC2 genes, accompanied by hyperactivation of the mTOR signaling pathway, which is responsible for the regulation of growth, proliferation, cell survival, and autophagy. One of the main clinical symptoms of tuberous sclerosis is the formation of tubers in the brain. These formations are characterized by disorders of the cortical lamination, the appearance of abnormal neurons and severe gliosis. It is known that the presence of cortical tubers correlates with the development of neuropsychiatric disorders, including drug-resistant epilepsy. This article highlights the issues of molecular genetics of tuberous sclerosis, presents the histopathological characteristics of cortical tubers, considers mechanism of morphogenesis of cortical tubers, and also presents the data on relationship of these formations with the development of neurological manifestations and methods of their treatment.

Sequential perturbations to mouse corticogenesis following in utero maternal immune activation

In utero exposure to maternal immune activation (MIA) is an environmental risk factor for neurodevelopmental and neuropsychiatric disorders. Animal models provide an opportunity to identify mechanisms driving neuropathology associated with MIA. We performed time course transcriptional profiling of mouse cortical development following induced MIA via poly(I:C) injection at E12.5. MIA-driven transcriptional changes were validated via protein analysis, and parallel perturbations to cortical neuroanatomy were identified via imaging. MIA-induced acute upregulation of genes associated with hypoxia, immune signaling, and angiogenesis, by six hours following exposure. This acute response was followed by changes in proliferation, neuronal and glial specification, and cortical lamination that emerged at E14.5 and peaked at E17.5. Decreased numbers of proliferative cells in germinal zones and alterations in neuronal and glial populations were identified in the MIA-exposed cortex. Overall, paired transcriptomic and neuroanatomical characterization revealed a sequence of perturbations to corticogenesis driven by mid-gestational MIA.

Neuroserpin Is Strongly Expressed in the Developing and Adult Mouse Neocortex but Its Absence Does Not Perturb Cortical Lamination and Synaptic Proteome

Neuroserpin is a serine protease inhibitor that regulates the activity of tissue-type plasminogen activator (tPA) in the nervous system. Neuroserpin is strongly expressed during nervous system development as well as during adulthood, when it is predominantly found in regions eliciting synaptic plasticity. In the hippocampus, neuroserpin regulates developmental neurogenesis, synaptic maturation and in adult mice it modulates synaptic plasticity and controls cognitive and social behavior. High expression levels of neuroserpin in the neocortex starting from prenatal stage and persisting during adulthood suggest an important role for the serpin in the formation of this brain region and in the maintenance of cortical functions. In order to uncover neuroserpin function in the murine neocortex, in this work we performed a comprehensive investigation of its expression pattern during development and in the adulthood. Moreover, we assessed the role of neuroserpin in cortex formation by comparing cortical lamination and neuronal maturation between neuroserpin-deficient and control mice. Finally, we evaluated a possible regulatory role of neuroserpin at cortical synapses in neuroserpin-deficient mice. We observed that neuroserpin is expressed starting from the beginning of corticogenesis until adulthood throughout the neocortex in several classes of glutamatergic projection neurons and GABA-ergic interneurons. However, in the absence of neuroserpin we did not detect any alteration either in cortical layer formation, or in neuronal soma size and dendritic length. Furthermore, no significant quantitative changes were observed in the proteome of cortical synapses upon neuroserpin deficiency. We conclude that, although strongly expressed in the neocortex, absence of neuroserpin does not lead to gross developmental abnormalities, and does not perturb the composition of the cortical synaptic proteome.

A Case of Agyria-Pachygyria Presenting as Seizure Disorder in A Young Girl

“Lissencephaly”, a rare gene linked defective neuroblast migration disorder resulting in defective cortical lamination, abnormal gyral development and subcortical heterotropia. Advances in molecular genetics have led to the identification of lissencephaly gene on chromosome 17p13.3 and causing Type-1 Lissencephaly or miller Diecker syndrome where lissencephaly is severe in posterior brain region. Another X-linked gene Doublecortin (DCX) gene where the lissencephaly is more severe in anterior region of the brain. Usually this defect manifests in early infancy or childhood as seizure disorder. A case of lissencephaly with features of Miller Dieker syndrome in a young girl is reported and literature is reviewed. The important feature of the case was its late presentation in a 17 years old girl.

MCF2 is linked to a complex perisylvian syndrome and affects cortical lamination

The combination of congenital bilateral perisylvian syndrome (CBPS) with lower motor neuron dysfunction is unusual and suggests a potential common genetic insult affecting basic neurodevelopmental processes. Here we identify a putatively pathogenic missense mutation in the MCF2 gene in a boy with CBPS. Using in utero electroporation to genetically manipulate cortical neurons during corticogenesis, we demonstrate that the mouse Mcf2 gene controls the embryonic migration of cortical projection neurons. Strikingly, we find that the CBPS-associated MCF2 mutation impairs cortical laminar positioning, supporting the hypothesis that alterations in the process of embryonic neuronal migration can lead to rare cases of CBPS.

Morphological and Physiological Characteristics of Ebf2-EGFP-Expressing Cajal-Retzius Cells in Developing Mouse Neocortex

Cajal-Retzius (CR) cells are one of the earliest populations of neurons in the cerebral cortex of rodents and primates, and they play a critical role in corticogenesis and cortical lamination during neocortical development. However, a comprehensive morphological and physiological profile of CR cells in the mouse neocortex has not yet been established. Here, we systematically investigated the dynamic development of CR cells in Tg(Ebf2-EGFP)58Gsat/Mmcd mice. The morphological complexity, membrane activities and presynaptic inputs of CR cells coordinately increase and reach a plateau at P5–P9 before regressing. Using 3D reconstruction, we delineated a parallel-stratification pattern of the axonal extension of CR cells. Furthermore, we found that the morphological structure and presynaptic inputs of CR cells were disturbed in Reelin-deficient mice. These findings confirm that CR cells undergo a transient maturation process in layer 1 before disappearing. Importantly, Reelin deficiency impairs the formation of synaptic connections onto CR cells. In conclusion, our results provide insights into the rapid maturation and axonal stratification of CR cells in layer 1. These findings suggest that both the electrophysiological activities and the morphology of CR cells provide vital guidance for the modulation of early circuits, in a Reelin-dependent manner.

Bi-allelic variants inCOL3A1encoding the ligand to GPR56 are associated with cobblestone-like cortical malformation, white matter changes and cerebellar cysts

BackgroundCollagens are one of the major constituents of the pial membrane, which plays a crucial role in neuronal migration and cortical lamination during brain development. Type III procollagen, the chains of which are encoded byCOL3A1, is the ligand of the G protein-coupled receptor 56 (GPR56), also known as adhesion G protein-coupled receptor G1. Bi-allelic mutations inGPR56give rise to cobblestone-like malformation, white matter changes and cerebellar dysplasia. This report shows that bi-allelic mutations inCOL3A1are associated with a similar phenotype.MethodsExome analysis was performed in a family consisting of two affected and two non-affected siblings. Brain imaging studies of this family and of two previously reported individuals with bi-allelic mutations inCOL3A1were reviewed. Functional assays were performed on dermal fibroblasts.ResultsExome analysis revealed a novel homozygous variant c.145C>G (p.Pro49Ala) in exon 2 ofCOL3A1. Brain MRI in the affected siblings as well as in the two previously reported individuals with bi-allelicCOL3A1mutations showed a brain phenotype similar to that associated with mutations inGPR56.ConclusionHomozygous or compound heterozygous mutations inCOL3A1are associated with cobblestone-like malformation in all three families reported to date. The variability of the phenotype across patients suggests that genetic alterations in distinct domains of type III procollagen can lead to different outcomes. The presence of cobblestone-like malformation in patients with bi-allelicCOL3A1mutations emphasises the critical role of the type III collagen–GPR56 axis and the pial membrane in the regulation of brain development and cortical lamination.