title: Microglia-dependent alteration of glutamatergic synaptic transmission and plasticity in the hippocampus during peripheral inflammation.
abstract: Peripheral inflammatory diseases are often associated with behavioral comorbidities including anxiety, depression, and cognitive dysfunction, but the mechanism for these is not well understood. Changes in the neuronal and synaptic functions associated with neuroinflammation may underlie these behavioral abnormalities. We have used a model of colonic inflammation induced by 2,4,6-trinitrobenzenesulfonic acid in Sprague Dawley rats to identify inflammation-induced changes in hippocampal synaptic transmission. Hippocampal slices obtained 4 d after the induction of inflammation revealed enhanced Schaffer collateral-induced excitatory field potentials in CA1 stratum radiatum. This was associated with larger-amplitude mEPSCs, but unchanged mEPSC frequencies and paired-pulse ratios, suggesting altered postsynaptic effects. Both AMPA- and NMDA-mediated synaptic currents were enhanced, and analysis of AMPA-mediated currents revealed increased contributions of GluR2-lacking receptors. In keeping with this, both transcripts and protein levels of the GluR2 subunit were reduced in hippocampus. Both long-term potentiation (LTP) and depression (LTD) were significantly reduced in hippocampal slices taken from inflamed animals. Chronic administration of the microglial/macrophage activation inhibitor minocycline to the inflamed animals both lowered the level of the cytokine tumor necrosis factor α in the hippocampus and completely abolished the effect of peripheral inflammation on the field potentials and synaptic plasticity (LTP and LTD). Our results reveal profound synaptic changes caused by a mirror microglia-mediated inflammatory response in hippocampus during peripheral organ inflammation. These synaptic changes may underlie the behavioral comorbidities seen in patients.
authors: Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors: Kiarash
authors: http://orcid.org/0000-0002-2291-7405
authors: K
authors: Riazi
authors: Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors: Michael A
authors: MA
authors: Galic
authors: Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors: Amanda C
authors: http://orcid.org/0000-0001-7069-486X
authors: AC
authors: Kentner
authors: Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors: Aylin Y
authors: AY
authors: Reid
authors: Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors: Keith A
authors: KA
authors: Sharkey
authors: Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1 pittman@ucalgary.ca.
authors: Quentin J
authors: http://orcid.org/0000-0003-0984-7665
authors: QJ
authors: Pittman
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D003106:Colon / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000502:physiology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D055369:Miniature Postsynaptic Potentials / Q000502:physiology; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism / Q000502:physiology*; D055366:Synaptic Potentials / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018091:Receptors, AMPA; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid; D008911:Minocycline; C104722:glutamate receptor ionotropic, AMPA 2
keywords: LTD; LTP; cytokine; glutamate; microglia; neuroinflammation