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Lipoprotein receptor loss in forebrain radial glia results in neurological deficits and severe seizures
Author(s) -
Bres Ewa E.,
Safina Dina,
Müller Julia,
Bedner Peter,
Yang Honghong,
Helluy Xavier,
Shchyglo Olena,
Jansen Stephan,
Mark Melanie D.,
Esser Alexander,
Steinhäuser Christian,
Herlitze Stefan,
Pietrzik Claus U.,
Sirko Swetlana,
ManahanVaughan Denise,
Faissner Andreas
Publication year - 2020
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.23869
Subject(s) - biology , gliosis , neuroscience , lrp1 , astrocyte , forebrain , receptor , ldl receptor , lipoprotein , endocrinology , central nervous system , genetics , cholesterol
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.