Fractalkine/CX3CR1-Dependent Modulation of Synaptic and Network Plasticity in Health and Disease

Abstract

CX3CR1 is a G protein-coupled receptor that is expressed exclusively by microglia within the brain parenchyma. The only known physiological CX3CR1 ligand is the chemokine fractalkine (FKN), which is constitutively expressed in neuronal cell membranes and tonically released by them. Through its key role in microglia-neuron communication, the FKN/CX3CR1 axis regulates microglial state, neuronal survival, synaptic plasticity, and a variety of synaptic functions, as well as neuronal excitability via cytokine release modulation, chemotaxis, and phagocytosis. Thus, the absence of CX3CR1 or any failure in the FKN/CX3CR1 axis has been linked to alterations in different brain functions, including changes in synaptic and network plasticity in structures such as the hippocampus, cortex, brainstem, and spinal cord. Since synaptic plasticity is a basic phenomenon in neural circuit integration and adjustment, here, we will review its modulation by the FKN/CX3CR1 axis in diverse brain circuits and its impact on brain function and adaptation in health and disease.

Figure 1

Microglia regulate hippocampal LTP through FXN/CX3CR1 signaling. (a) After high-frequency stimulation (HFS), increased glutamate release overactivates AMPAR but mostly NMDAR, inducing hippocampal long-term potentiation (LTP). (b) Microglia communicate with neurons through CX3CR1, inducing synapse remodeling and promoting plasticity. The lack of CX3CR1 impairs synaptic remodeling and engulfment and spine formation. (c) After HFS, neurons release FKN to activate microglial CX3CR1, leading to the synthesis and release of neurotrophic factors (BDNF) and cytokines, which can enhance (↑) or inhibit (↓) hippocampal LTP. The lack of CX3CR1 or FKN inhibits LTP, which is related to the exacerbated release of IL-1β and TNF-α.

Figure 2

Neuropathic pain and spinal plasticity are modulated by microglial CX3CR1. (a) Neuropathic pain has been studied using several models including nerve high-frequency stimulation (HFS), chronic constriction injury (CCI), sciatic nerve ligation (SNL), sciatic axotomy (SA), and sciatic nerve injury (SNI). These models converge in the activation of spinal microglia. (b) Microglial activation leads to the release of cathepsin S (CatS), which induces the release of fractalkine (FKN) from dorsal horn neurons and its binding to microglial CX3CR1. The activation of CX3CR1 recruits p38 MAP kinase (p38MAPK), which is involved in the release of cytokines and neurotrophic factors that participate in the induction and maintenance of spinal long-term potentiation (LTP) and/or nociceptive facilitation. DRG: dorsal root ganglion; AMPAR and NMDAR: glutamate receptors; IL: interleukin; BDNF: brain-derived neurotrophic factor; TNF-α: tumor necrosis factor alpha.