Reelin and ApoE Receptors Cooperate to Enhance Hippocampal Synaptic Plasticity and Learning

TLDR

Reelin, a signaling protein that binds the VLDL receptor and apoER2, is expressed by GABA‑ergic interneurons in the adult brain and its receptors have been linked to memory and Alzheimer disease. The study investigates the role of Reelin and its receptors in cognition and synaptic plasticity. The authors employed VLDL receptor and apoER2 knockout mice to probe this role. Mice lacking VLDL receptor or apoER2 exhibit contextual fear conditioning deficits and impaired LTP, while Reelin application enhances CA1 LTP in wild‑type slices but not in knockouts, demonstrating that Reelin‑dependent plasticity requires both receptors and may underlie cognitive decline in Alzheimer disease.

Abstract

Two apolipoprotein E (apoE) receptors, the very low density lipoprotein (VLDL) receptor and apoE receptor 2 (apoER2), are also receptors for Reelin, a signaling protein that regulates neuronal migration during brain development. In the adult brain, Reelin is expressed by GABA-ergic interneurons, suggesting a potential function as a modulator of neurotransmission. ApoE receptors have been indirectly implicated in memory and neurodegenerative disorders because their ligand, apoE, is genetically associated with Alzheimer disease. We have used knockout mice to investigate the role of Reelin and its receptors in cognition and synaptic plasticity. Mice lacking either the VLDL receptor or the apoER2 show contextual fear conditioning deficits. VLDL receptor-deficient mice also have a moderate defect in long term potentiation (LTP), and apoER2 knockouts have a pronounced one. The perfusion of mouse hippocampal slices with Reelin has no effect on baseline synaptic transmission but significantly enhances LTP in area CA1. This Reelin-dependent augmentation of LTP is abolished in VLDL receptor and apoER2 knockout mice. Our results reveal a role for Reelin in controlling synaptic plasticity in the adult brain and suggest that both of its receptors are necessary for Reelin-dependent enhancement of synaptic transmission in the hippocampus. Thus, the impairment of apoE receptor-dependent neuromodulation may contribute to cognitive impairment and synaptic loss in Alzheimer disease.