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Lipoprotein receptor loss in forebrain radial glia results in neurological deficits and severe seizures.
Glia 68, 2517-2549 (2020)
The Alzheimer disease-associated multifunctional low-density lipoprotein receptor-related protein-1 is expressed in the brain. Recent studies uncovered a role of this receptor for the appropriate functioning of neural stem cells, oligodendrocytes, and neurons. The constitutive knock-out (KO) of the receptor is embryonically lethal. To unravel the receptors' role in the developing brain we generated a mouse mutant by specifically targeting radial glia stem cells of the dorsal telencephalon. The low-density lipoprotein receptor-related protein-1 lineage-restricted KO female and male mice, in contrast to available models, developed a severe neurological phenotype with generalized seizures during early postnatal development. The mechanism leading to a buildup of hyperexcitability and emergence of seizures was traced to a failure in adequate astrocyte development and deteriorated postsynaptic density integrity. The detected impairments in the astrocytic lineage: precocious maturation, reactive gliosis, abolished tissue plasminogen activator uptake, and loss of functionality emphasize the importance of this glial cell type for synaptic signaling in the developing brain. Together, the obtained results highlight the relevance of astrocytic low-density lipoprotein receptor-related protein-1 for glutamatergic signaling in the context of neuron-glia interactions and stage this receptor as a contributing factor for epilepsy.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Astrocytes ; Epilepsy ; Lipoprotein Receptor-related Protein ; Radial Glia Stem Cells ; Reactive Astrocytes ; Seizures ; Tissue Plasminogen Activator; Methyl-d-aspartate; Tissue-plasminogen Activator; Immediate-early Gene; Conditional Deletion; Glutamate Uptake; Protein-1 Lrp1; Mouse Model; Brain; Expression; Astrocytes
ISSN (print) / ISBN 0894-1491
Quellenangaben Volume: 68, Issue: 12, Pages: 2517-2549
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Reviewing status Peer reviewed
Institute(s) Institute of Stem Cell Research (ISF)