Cellular, synaptic, and network effects of chemokines in the central nervous system and their implications to behavior

Accumulating evidence highlights chemokines as key mediators of the bidirectional crosstalk between neurons and glial cells aimed at preserving brain functioning. The multifaceted role of these immune proteins in the CNS is mirrored by the complexity of the mechanisms underlying its biological function, including biased signaling. Neurons, only in concert with glial cells, are essential players in the modulation of brain homeostatic functions. Yet, attempts to dissect these complex multilevel mechanisms underlying coordination are still lacking. Therefore, the purpose of this review is to summarize the current knowledge about mechanisms underlying chemokine regulation of neuron–glia crosstalk linking molecular, cellular, network, and behavioral levels. Following a brief description of molecular mechanisms by which chemokines interact with their receptors and then summarizing cellular patterns of chemokine expression in the CNS, we next delve into the sequence and mechanisms of chemokine-regulated neuron–glia communication in the context of neuroprotection. We then define the interactions with other neurotransmitters, neuromodulators, and gliotransmitters. Finally, we describe their fine-tuning on the network level and the behavioral relevance of their modulation. We believe that a better understanding of the sequence and nature of events that drive neuro-glial communication holds promise for the development of new treatment strategies that could, in a context- and time-dependent manner, modulate the action of specific chemokines to promote brain repair and reduce the neurological impairment.