Differential splicing and glycosylation of Apoer2 alters synaptic plasticity and fear learning

Abstract

Apoer2 is an essential receptor in the central nervous system that binds to the apolipoprotein ApoE. Various splice variants of Apoer2 are produced. We showed that Apoer2 lacking exon 16, which encodes the O-linked sugar (OLS) domain, altered the proteolytic processing and abundance of Apoer2 in cells and synapse number and function in mice. In cultured cells expressing this splice variant, extracellular cleavage of OLS-deficient Apoer2 was reduced, consequently preventing γ-secretase-dependent release of the intracellular domain of Apoer2. Mice expressing Apoer2 lacking the OLS domain had increased Apoer2 abundance in the brain, hippocampal spine density, and glutamate receptor abundance, but decreased synaptic efficacy. Mice expressing a form of Apoer2 lacking the OLS domain and containing an alternatively spliced cytoplasmic tail region that promotes glutamate receptor signaling showed enhanced hippocampal long-term potentiation (LTP), a phenomenon associated with learning and memory. However, these mice did not display enhanced spatial learning in the Morris water maze, and cued fear conditioning was reduced. Reducing the expression of the mutant Apoer2 allele so that the abundance of the protein was similar to that of Apoer2 in wild-type mice normalized spine density, hippocampal LTP, and cued fear learning. These findings demonstrated a role for ApoE receptors as regulators of synaptic glutamate receptor activity and established differential receptor glycosylation as a potential regulator of synaptic function and memory.

Reelin protects against amyloid β toxicity in vivo

“…Finally, Reelin activation of Apoer2 initiates a transcriptional program through CREB that underlies learning and memory (8, 61, 62). Loss of this transcriptional program may be a cause for the synaptic and electrophysiological alterations we observed(4). …”

“…200 μm thick slices were acquired by vibratome (4). Z-sections of the Golgi-stained brains were acquired to measure the spine density of CA1 apical dendrites.…”

The ApoE receptors Vldlr and Apoer2 in central nervous system function and disease

“…At the same time, the ECD can act as a dominant-negative ligand to inhibit Reelin signaling (55). When the OLS is glycosylated or excluded by alternatively splicing, Apoer2 is protected from proteolytic processing (7,56). This leads both to an abundance of Apoer2 and a reduction in these negative-feedback mechanisms (56).…”

Spinal Cord Stimulation Alters Protein Levels in the Cerebrospinal Fluid of Neuropathic Pain Patients: A Proteomic Mass Spectrometric Analysis

“…We detected 36% average increase of apolipoprotein E in the SCSON condition which might be linked to neural plasticity. Apolipoprotein E receptors have recently been shown to regulate synaptic glutamate receptor activity, and their glycosylation may alter synaptic function and memory . Apolipoprotein E receptor 2 contributes to enhanced synaptic plasticity and learning and it is physically and functionally coupled to NMDA receptors at postsynaptic density of hippocampal synapses .…”