Organelle and Cellular Abnormalities Associated with Hippocampal Heterotopia in Neonatal Doublecortin Knockout Mice

Abstract

Heterotopic or aberrantly positioned cortical neurons are associated with epilepsy and intellectual disability. Various mouse models exist with forms of heterotopia, but the composition and state of cells developing in heterotopic bands has been little studied. Dcx knockout (KO) mice show hippocampal CA3 pyramidal cell lamination abnormalities, appearing from the age of E17.5, and mice suffer from spontaneous epilepsy. The Dcx KO CA3 region is organized in two distinct pyramidal cell layers, resembling a heterotopic situation, and exhibits hyperexcitability. Here, we characterized the abnormally organized cells in postnatal mouse brains. Electron microscopy confirmed that the Dcx KO CA3 layers at postnatal day (P) 0 are distinct and separated by an intermediate layer devoid of neuronal somata. We found that organization and cytoplasm content of pyramidal neurons in each layer were altered compared to wild type (WT) cells. Less regular nuclei and differences in mitochondria and Golgi apparatuses were identified. Each Dcx KO CA3 layer at P0 contained pyramidal neurons but also other closely apposed cells, displaying different morphologies. Quantitative PCR and immunodetections revealed increased numbers of oligodendrocyte precursor cells (OPCs) and interneurons in close proximity to Dcx KO pyramidal cells. Immunohistochemistry experiments also showed that caspase-3 dependent cell death was increased in the CA1 and CA3 regions of Dcx KO hippocampi at P2. Thus, unsuspected ultrastructural abnormalities and cellular heterogeneity may lead to abnormal neuronal function and survival in this model, which together may contribute to the development of hyperexcitability.

Differential Mitochondrial Requirements for Radially and Non-radially Migrating Cortical Neurons: Implications for Mitochondrial Disorders

“…Previous work has shown that Lis1, Tau 1, and DCX, genes that cause defects in radial migration and IN development, cause mislocalized and altered mitochondrial trafficking (Khalaf-Nazzal et al, 2013; Sapir et al, 2012; Yamada et al, 2009). Although this suggests that defects in mitochondrial localization may also impact PNs, each of these genes also regulates microtubule dynamics.…”

Adverse Outcome Pathway on inhibition of Thyroperoxidase and subsequent adverse neurodevelopmental outcomes in mammals

“…Work supporting the relationship includes use of a variety of animal models (i.e., nutritional deficiencies, chromosome abnormalities, gene deletions, knock out animals, toxicant exposures and developmental hormonal imbalance) (e.g., Frotscher, 2010;Castren and Castren, 2014;Skucas et al, 2011;Lessman et al, 2011). Mutant mouse lines generated for genes involved in human cortical malformations such as doublecortin, reelin, Lis1 and Tuba1a also show gross disorganization within the hippocampus (Khalaf-Nazzal et al, 2013). Collectively, data from these studies clearly support the link between alterations in hippocampal gene expression and structural changes in hippocampal volume, cell number, and/or cytoarchitecture.…”

“…Collectively, data from these studies clearly support the link between alterations in hippocampal gene expression and structural changes in hippocampal volume, cell number, and/or cytoarchitecture. A direct linkage between some specific gene targets and structural change in the hippocampus has been demonstrated using knock out and mutant mouse models (e.g., Lee et al, 2000;Frotscher, 2010;Castren and Castren, 2014;Skucas et al, 2011;Lessman et al, 2011;Khalaf-Nazzal et al, 2013).…”

Correlation of changes of (non)exfoliated endometrial organelles and expressions of Musashi-1 and β-catenin with endometriosis in menstrual period

“…In 2010, Liu & Lang [6] proposed the eutopic endometrial decision theory; the endometrial cells must complete the trilogy of attachment, aggression and angiogenesis, namely ''3 A'' pathogenetic mode. In 2011, Khalaf-Nazzal et al [7] found ultrastructural abnormalities and cellular heterogeneity may lead to abnormal neuronal function. Klemmer et al [8] proposed that alterations of presynaptic structure in the Fmr 1 KO mouse, contributing to the underlying molecular basis of hippocampal deficits in Fragile X syndrome.…”