title: Activation of toll like receptor 4 attenuates GABA synthesis and postsynaptic GABA receptor activities in the spinal dorsal horn via releasing interleukin-1 beta.
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.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, 240 West Green Street, Athens, GA, 30602, USA. xisheng@uga.edu.|Department of Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. xisheng@uga.edu.|Department of Cardiovascular Medicine, the Third Hospital of Wuhan, Wuhan, Hubei Province, China. xisheng@uga.edu.
authors.forename: Xisheng
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. esjiang@gmail.com.|Institute of Public Hygiene, Henan University Nursing School, Kaifeng, China. esjiang@gmail.com.
authors.forename: Enshe
authors.initials: E
authors.lastname: Jiang
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia College of Pharmacy, 240 West Green Street, Athens, GA, 30602, USA. hrweng@uga.edu.|Department of Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. hrweng@uga.edu.
authors.forename: Han-Rong
authors.initials: HR
authors.lastname: Weng
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008911:Minocycline / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D018079:Receptors, GABA / Q000378:metabolism*; D066148:Spinal Cord Dorsal Horn / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D027322:Amino Acid Transport System X-AG; D004791:Enzyme Inhibitors; D018683:Excitatory Amino Acid Agents; D018682:GABA Agents; D005904:Glial Fibrillary Acidic Protein; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D018079:Receptors, GABA; D051197:Toll-Like Receptor 4; D005680:gamma-Aminobutyric Acid; D008911:Minocycline