Cytokines and cytokine networks target neurons to modulate long-term potentiation

Abstract

Cytokines play crucial roles in the communication between brain cells including neurons and glia, as well as in the brain-periphery interactions. In the brain, cytokines modulate long-term potentiation (LTP), a cellular correlate of memory. Whether cytokines regulate LTP by direct effects on neurons or by indirect mechanisms mediated by non-neuronal cells is poorly understood. Elucidating neuron-specific effects of cytokines has been challenging because most brain cells express cytokine receptors. Moreover, cytokines commonly increase the expression of multiple cytokines in their target cells, thus increasing the complexity of brain cytokine networks even after single-cytokine challenges. Here, we review evidence on both direct and indirect-mediated modulation of LTP by cytokines. We also describe novel approaches based on neuron- and synaptosome-enriched systems to identify cytokines able to directly modulate LTP, by targeting neurons and synapses. These approaches can test multiple samples in parallel, thus allowing the study of multiple cytokines simultaneously. Hence, a cytokine networks perspective coupled with neuron-specific analysis may contribute to delineation of maps of the modulation of LTP by cytokines.

Keywords: FASS-LTP; Hippocampus; Inflammation; LTP; Synapse.

Fig. 1

Cytokines and cytokine networks modulate LTP by targeting synapses. This simplified model illustrates LTP, which relies on the NMDAR-dependent insertion of GluA1-containing AMPA receptors at the postsynaptic surface. In this model communication via cytokines is depicted by arrows, which can bi-directionally connect multiple cell populations. Cytokine networks enable local interactions between neuronal and non-neuronal cells (e.g., astrocytes, microglia, vascular endothelial cells) in the brain, as well as brain-periphery communication via the brain-blood barrier (BBB) and the choroid plexus (CP). The BBB releases cytokines and regulates the flux of cytokines from the blood; the CP produces cerebrospinal fluid (CSF) and cytokines, and regulates the transport of cytokines and immune cells from blood vessels. LTP modulation by cytokines has been widely studied, however, for most cytokines, is unclear if they modulate LTP by directly targeting synapses (one-direction arrows) or by indirect mechanisms relying on cytokine networks maintained by non-neuronal cells interactions. Cytokines can induce the expression and release of multiple cytokines in their target cells, thus activating cytokine networks, which could modulate synaptic transmission by targeting synapses via both cytokine-dependent and -independent mechanisms (dotted arrows).

Fig. 2

Multiplex analysis of cytokine-mediated modulation of LTP directly at the synapse using FASS-LTP. The synaptosome-enriched fraction (P2 fraction) can be rapidly isolated to study synapse-specific effects of cytokines. After isolation, synaptosomes can be treated with cytokines (1) before cLTP (2), which is induced by NMDAR activation using glycine (white triangle) and KCl depolarization. Cytokine treatment and cLTP is followed by immunolabeling for surface (no permeabilization) GluA1 (3) to identify potentiated synapses. Finally, flow cytometry identifies potentiated synapses by size and GluA1 labeling (4) (see details in (56)). A key advantage of this approach is the possibility of testing multiple agents in parallel (~ 40, (80)).