TrkB/mGluR5 cross-talk underlies a synaptic metaplasticity mechanism of ketamine.

Summary

The antidepressant effects of ketamine rely on the interaction between the tropomyosin-related kinase B (TrkB) receptor and the metabotropic glutamate receptor 5 (mGluR5). mGluR5 enhances signaling from brain-derived neurotrophic factor (BDNF) to TrkB, promoting synaptic strengthening, while BDNF's activation of TrkB leads to mGluR5 endocytosis, which hinders synaptic weakening. Ketamine boosts these interactions, and an mGluR5 positive allosteric modulator can further enhance their effects.

Study at a glance

Abstract

A complex ensemble of neuromodulatory receptors orchestrates the many forms of synaptic plasticity that drive behavioral state changes, but an understanding of how such receptors functionally interact is limited. Here, we find that the antidepressant action of ketamine is dependent on both the receptor tyrosine kinase, tropomyosin-related kinase B (TrkB), and the G protein-coupled receptor, metabotropic glutamate receptor 5 (mGluR5). mGluR5 amplifies brain-derived neurotrophic factor (BDNF)-driven signaling of TrkB, enabling synaptic potentiation via "signaling cross-talk," while BDNF activation of TrkB drives mGluR5 endocytosis via "trafficking cross-talk," impairing synaptic depression. These modes of cross-talk are enhanced by ketamine, which increases surface and postsynaptic levels of TrkB. Last, we find that an mGluR5 positive allosteric modulator can enhance both modes of cross-talk and boost the effects of ketamine. Together, these data unravel the intimate relationship between different classes of neuromodulatory receptors, revealing that receptor-receptor interplay can drive therapeutic action.