B6;129S-Lrp8^tm3Her/J

Stock number: 025755
Research areas: Neurobiology Research

Description

These Lrp8 knockin mice constitutively express a nonspliceable alternative transcript incorporating exons 17, 18, and 20 (not exon 19) and are useful in studies of neurotransmission.

Detailed description

Lrp8 (low density lipoprotein receptor-related protein 8; also called Apoer2, apolipoprotein E receptor 2) is a member of the low density lipoprotein (LDL) receptor gene family. In association with its ligand, RELN (reelin), it controls neuronal migration during brain development. It is also essential for induction of long-term potentiation (LTP) in the adult brain. Alternative splicing involving exon 19 controls RELN-mediated modulation of N-methyl-D-aspartate (NMDA) receptor activity, synaptic neurotransmission and memory processes.

In this targeted knock-in strain, a knockin of exons 17, 18 and 20 of the mouse Lrp8 gene is constitutively expressed from the native promoter to create a model of nonspliceable alternative transcript activity.

Mice constitutively expressing transcripts derived from exons 17, 18, and 20 (but not exon 19) are deficient in learning and memory tasks. Exon 19 is also required for the modulation of LTP, NMDA receptor phosphorylation, and synaptic plasticity through interactions with RELN. Knockin mice that constitutively express exon 19 (see Stock No. 022867) show robust RELN-dependent increases in LTP induction that are completely abrogated in these knockin mice lacking exon 19. This evidence suggests that exon 19 is required for RELN-enhanced LTP. Unlike animals constitutively expressing transcripts that include exon 19, these knockin animals show no RELN-induced elevation of NMDA receptor-dependent potentials above baseline synaptic responses. They also demonstrate a highly significant reduction in contextual fear conditioning as measured by reduced freezing behavior following a reintroduction to the same environment where they previously received a mild foot shock.

Development

Exons 17, 18 and 20 (not exon 19) of the mouse Lrp8 gene followed by a loxP-flanked neomycin cassette were knocked into/replace the endogenous exon 17 of the gene to create a constitutively-expressed, nonspliceable alternative transcript. The mutation was created through homologous recombination in 129S6/SvEvTac-derived SM1 embryonic stem (ES) cells. Resultant male chimeric mice were crossed C57BL/6J females to establish germline transmission. Animals were subsequently bred with germline Meox2-cre animals (see Stock No. 003755) to excise the neomycin cassette. This strain was maintained on a mixed C57BL/6 and 129 genetic background by the donating laboratory.

Allele

Symbol: Lrp8^tm3Her
Name: targeted mutation 3, Joachim Herz
MGI accession ID: MGI:3603434
Generation method: Targeted
Attributes: Modified isoform(s)
Marker symbol: Lrp8
Marker name: low density lipoprotein receptor-related protein 8, apolipoprotein e receptor
Chromosome: 4
Strain of origin: 129S6/SvEvTac
Molecular note: A targeting vector containing exons 17-20 and a downstream loxP-flanked neomycin cassette encoding the intracellular domain without exon 19 was inserted into the locus such that the locus constitutively expressed transcript without the 59 amino acid insert encoded by exon 19. Cre-mediated recombination removed the neomycin cassette.