Research ArticleNeuroscience

Ligand-independent activity of the ghrelin receptor modulates AMPA receptor trafficking and supports memory formation

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Science Signaling  16 Feb 2021:
Vol. 14, Issue 670, eabb1953
DOI: 10.1126/scisignal.abb1953

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No ligand needed for learning

In addition to its role in stimulating appetite, the hormone ghrelin and its receptor GHS-R1a are implicated in cognition. Ribeiro et al. found a role for ghrelin-independent GHS-R1a signaling in learning in mice. The use of inverse agonists and mutants revealed that ligand-independent activity of GHS-R1a maintained the synaptic abundance of AMPA-type glutamate receptors in hippocampal neurons through a phosphorylation-dependent trafficking mechanism in cultured neurons and brain slices, thereby ensuring tonic control of synaptic plasticity. Treating mice with a GHS-R1a inverse agonist impaired spatial and contextual memory formation. Thus, the use of ghrelin receptor–blocking therapies—which have been proposed for treating metabolic disorders, acromegaly, cancer, and alcoholism—may also have cognitive side effects.

Abstract

The biological signals of hunger, satiety, and memory are interconnected. The role of the hormone ghrelin in regulating feeding and memory makes ghrelin receptors attractive targets for associated disorders. We investigated the effects of the high ligand-independent activity of the ghrelin receptor GHS-R1a on the physiology of excitatory synapses in the hippocampus. Blocking this activity produced a decrease in the synaptic content of AMPA receptors in hippocampal neurons and a reduction in GluA1 phosphorylation at Ser845. Reducing the ligand-independent activity of GHS-R1a increased the surface diffusion of AMPA receptors and impaired AMPA receptor–dependent synaptic delivery induced by chemical long-term potentiation. Accordingly, we found that blocking this GHS-R1a activity impaired spatial and recognition memory in mice. These observations support a role for the ligand-independent activity of GHS-R1a in regulating AMPA receptor trafficking under basal conditions and in the context of synaptic plasticity that underlies learning.

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