Crosstalk between glial Cx43 and neuronal Panx1 and P2X7 receptors modulate presynaptic homeostatic plasticity

Abstract

Abstract The emerging role of glial cells in the modulation of neuronal excitability and synaptic strength is a growing field in neuroscience. An increased number of studies indicate that gliotransmission is mediated by both the classical Ca2+-dependent release and the non-vesicular route mediated by connexin and pannexin hemichannels. Recent reports highlighted the role of gliotransmission in the homeostatic adjustment of synaptic strength. In particular, glial-derived ATP arises as a key mediator in this process. However, very little is known about the glial non-vesicular ATP-release pathway and how this ATP could participate in the modulation of synaptic strength. Here we investigated the functional changes occurring in the presynaptic terminal and the role of the purinergic signaling, connexin43 and pannexin1 hemichannels in this process. By using hippocampal dissociated cultures, we show that glial connexin43-dependent ATP release triggers the homeostatic adjustment of presynaptic remodeling and function upon chronic activity silencing. Notably, activated neuronal P2X7Rs play an essential role in this process by mediating the entrance of Ca2+ to the presynaptic cell; our data also suggest that the functional crosstalk between neuronal P2X7Rs and pannexin1 hemichannels is required for the compensatory adjustment of presynaptic function. Interestingly, we show that neuronal permeability is regulated during chronic inactivity and, in particular, we found that neuronal pannexin1 hemichannels are gradually opened, increasing their activity upon 12h of neuronal inactivity. Hence, our results show for the first time the glial-dependent changes occurring in the presynaptic terminal upon chronic activity silencing and highlight the role of the interaction between presynaptic P2X7Rs and pannexin1 in the homeostatic adjustment of presynaptic strength.