Lipoprotein receptor loss in forebrain radial glia results in neurological deficits and severe seizures.

Abstract:

: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.

journal_name

Glia

journal_title

Glia

authors

Bres EE,Safina D,Müller J,Bedner P,Yang H,Helluy X,Shchyglo O,Jansen S,Mark MD,Esser A,Steinhäuser C,Herlitze S,Pietrzik CU,Sirko S,Manahan-Vaughan D,Faissner A

doi

10.1002/glia.23869

subject

Has Abstract

pub_date

2020-12-01 00:00:00

pages

2517-2549

issue

12

eissn

0894-1491

issn

1098-1136

journal_volume

68

pub_type

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