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.
