Abstract
Neurons that lose part of their afferent input remodel their synaptic connections. While cellular and molecular mechanisms of denervation-induced changes in excitatory neurotransmission have been identified, little is known about the signaling pathways that control inhibition in denervated networks. In this study, we used mouse entorhino-hippocampal tissue cultures of both sexes to study the role of the pro-inflammatory cytokine tumor necrosis factor α (TNFα) in denervation-induced plasticity of inhibitory neurotransmission. In line with our previous findings in vitro, an entorhinal cortex lesion triggered a compensatory increase in the excitatory synaptic strength of partially denervated dentate granule cells. Inhibitory synaptic strength was not changed 3 days after the lesion. These functional changes were accompanied by a recruitment of microglia in the denervated hippocampus, and experiments in tissue cultures prepared from TNF-reporter mice [C57BL/6-Tg(TNFa-eGFP)] showed increased TNFα expression in the denervated zone. However, inhibitory neurotransmission was not affected by scavenging TNFα with a soluble TNF receptor. In turn, a decrease in inhibition, i.e., decreased frequencies of miniature inhibitory postsynaptic currents, was observed in denervated dentate granule cells of microglia-depleted tissue cultures. We conclude from these results that activated microglia maintain the inhibition of denervated dentate granule cells and that TNFα is not required for the maintenance of inhibition after denervation.
Highlights
The balance of excitation and inhibition is essential for the proper function and for information processing in cortical circuits [1,2,3]
The results of this study show that scavenging tumor necrosis factor α (TNFα) for 3 days with soluble TNFα receptor (sTNFR) does not affect inhibitory synapses, i.e., mIPSC properties, in cultured dentate granule cells, both under control conditions and following partial denervation
A denervationinduced reduction in inhibition, i.e., decreased mean mIPSC frequency, is observed when microglia are depleted from tissue cultures
Summary
The balance of excitation and inhibition is essential for the proper function and for information processing in cortical circuits [1,2,3]. While feedforward and feedback circuits dynamically match recruited inhibition to afferent excitation and local network activity, synaptic plasticity maintains this balance over longer periods of time [4]. Work from the past two decades has identified several cellular and molecular mechanisms that mediate and modulate the ability of neurons to express the homeostatic plasticity of excitatory and inhibitory neurotransmission [7,8,9]. The biological significance of homeostatic synaptic changes that occur under pathological conditions such as brain injury and neurodegeneration remains elusive. We theorized that mechanisms exist that maintain the GABAergic synaptic set-point by preventing its homeostatic adjustment, i.e., denervation-induced downscaling of inhibition, even under conditions in which neurons cannot compensate via changes in excitatory neurotransmission
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