Abstract
Toll like receptor 4 (TLR4) is an innate immune pattern recognition receptor, expressed predominantly on microglia in the CNS. Activation of spinal TLR4 plays a critical role in the genesis of pathological pain induced by nerve injury, bone cancer, and tissue inflammation. Currently, it remains unknown how synaptic activities in the spinal dorsal horn are regulated by TLR4 receptors. Through recording GABAergic currents in neurons and glial glutamate transporter currents in astrocytes in rodent spinal slices, we determined whether and how TLR4 modulates GABAergic synaptic activities in the superficial spinal dorsal horn. We found that activation of TLR4 by lipopolysaccharide (LPS) reduces GABAergic synaptic activities through both presynaptic and postsynaptic mechanisms. Specifically, LPS causes the release of IL-1β from microglia. IL-1β in turn suppresses GABA receptor activities at the postsynaptic site through activating protein kinase C (PKC) in neurons. GABA synthesis at the presynaptic site is reduced upon activation of TLR4. Glial glutamate transporter activities are suppressed by IL-1β and PKC activation induced by LPS. The suppression of glial glutamate transporter activities leads to a deficiency of glutamine supply, which results in an attenuation of the glutamate-glutamine cycle-dependent GABA synthesis. These findings shed light on understanding synaptic plasticity induced by activation of TLR4 under neuroinflammation and identify GABA receptors, glial glutamate transporters, IL-1β and PKC as therapeutic targets to abrogate abnormal neuronal activities following activation of TLR4 in pathological pain conditions.
Highlights
Toll like reeptor 4 (TLR4) is an innate immune pattern recognition receptor, expressed predominantly on microglia in the central nervous system (CNS) [1,2]
LPS suppresses GABAergic inhibitory postsynaptic currents (IPSCs) through activating microglia To study the impact of TLR4 activation on GABAergic synaptic activities, GABAergic miniature GABAergic IPSCs (mIPSCs) were first recorded from neurons located in spinal lamina II in rats in the presence of 1 μM TTX before and after bath perfusion of the well-known TLR4 agonist LPS (1 μg/ml) [26]
To confirm that the minocycline treatment under our experimental conditions did not alter the GABAergic synaptic activities, we examined the effects of minocycline on GABAergic mIPSCs
Summary
Toll like reeptor 4 (TLR4) is an innate immune pattern recognition receptor, expressed predominantly on microglia in the CNS [1,2]. It is generally believed that pathological pain is a reflection of aberrant neuronal activities along the pain signaling pathway, which includes primary sensory neurons in the periphery, neurons in the spinal dorsal horn, and supraspinal areas in the central nervous system (CNS) [9]. Gamma-amino butyric acid (GABA) released from GABAergic interneurons inhibits neuronal activities through acting on GABA receptors at presynaptic terminals to reduce release of excitatory neurotransmitter (like glutamate), or acting on postsynaptic GABA receptors in neurons to produce inhibitory postsynaptic currents (IPSCs), or membrane hyperpolarization, in postsynaptic neurons [12]. Reduced neuronal inhibition, termed 'disinhibition', resulting from decreased GABAergic synaptic strength in the spinal dorsal horn is a crucial mechanism contributing to the development and maintenance of pathological pain [13,14,15]. Weakening of GABAergic synaptic strength may result from a reduction of the GABA transmitter release probability at the presynaptic site, attenuation of the GABA receptor function at the postsynaptic neurons, or impairment in GABA synthesis at the presynaptic site
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