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.
Highlights
Doublecortin (DCX) is mutated in subcortical band heterotopia (SBH), a severe human cortical malformation characterized by cortical neuronal somata present in the white matter
Well-organized and aligned CA3 pyramidal cell nuclei were identified in coronal semi-thin wild type (WT) P0 sections (Fig. 1A, C)
We found the developing Dcx KO pyramidal layers to be quite different from WT, being less organized and more heterogeneous
Summary
Doublecortin (DCX) is mutated in subcortical band heterotopia (SBH), a severe human cortical malformation characterized by cortical neuronal somata present in the white matter. Heterotopic neurons [1] are associated with epilepsy, and there is a strong correlation between drug-resistant forms and severe white matter heterotopia [2,3]. More recent data in rodent models of SBH suggest that the heterotopia, and the overlying cortex function abnormally [17]. Few studies have been devoted to characterizing the morphological and ultrastructural features of neurons developing in the heterotopic and overlying cortex. This could provide clues to their later abnormal function in the adult
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