Synaptic plasticity and cognitive function are disrupted in the absence of Lrp4

Abstract

Lrp4, the muscle receptor for neuronal Agrin, is expressed in the hippocampus and areas involved in cognition. The function of Lrp4 in the brain, however, is unknown, as Lrp4−/− mice fail to form neuromuscular synapses and die at birth. Lrp4−/− mice, rescued for Lrp4 expression selectively in muscle, survive into adulthood and showed profound deficits in cognitive tasks that assess learning and memory. To learn whether synapses form and function aberrantly, we used electrophysiological and anatomical methods to study hippocampal CA3–CA1 synapses. In the absence of Lrp4, the organization of the hippocampus appeared normal, but the frequency of spontaneous release events and spine density on primary apical dendrites were reduced. CA3 input was unable to adequately depolarize CA1 neurons to induce long-term potentiation. Our studies demonstrate a role for Lrp4 in hippocampal function and suggest that patients with mutations in Lrp4 or auto-antibodies to Lrp4 should be evaluated for neurological deficits.DOI: http://dx.doi.org/10.7554/eLife.04287.001

Presynaptic LRP4 promotes synapse number and function of excitatory CNS neurons

“…Though CNS LRP4 most commonly associates with postsynaptic densities (Tian et al, 2006), it also fractionates with synaptophysin-positive membranes (Gomez et al, 2014). Indeed, the observed CNS phenotypes have not been localized to a particular pool of LRP4.…”

“GAG-ing with the neuron”: The role of glycosaminoglycan patterning in the central nervous system

“…Lrp4 is expressed in the hippocampus and other areas of the brain involved in cognition. Lrp4 −/− mice fail to form neuromuscular synapses and die; however, rescuing muscular Lrp4 expression enables survival and the mice have a low spine density on primary apical dendrites, developing deficits in cognitive tasks including learning and memory (Gomez et al, 2014). Moreover, recently agrin mutations have been shown to lead to the rare condition called congenital myasthenic syndrome, which results from impaired neuromuscular transmission with distal muscle weakness and atrophy (Nicole et al, 2014).…”

ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease

“…A recent study used a mouse model in which Lrp4 is expressed in the muscle on an Lrp4 knockout background, permitting survival into adulthood. Importantly, these mice have a reduction of synaptic transmission and long-term potentiation [93], and this finding is mimicked in mice carrying a hypomorphic allele for Lrp4 [94]. A further study refined the role of Lrp4, inasmuch as it now appears that it is not neuronally expressed Lrp4, but rather astrocytic Lrp4 that mediates this process.…”