title: CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity.
abstract: The protective/neurotoxic role of fractalkine (CX3CL1) and its receptor CX3C chemokine receptor 1 (CX3CR1) signaling in neurodegenerative disease is an intricate and highly debated research topic and it is becoming even more complicated as new studies reveal discordant results. It appears that the CX3CL1/CX3CR1 axis plays a direct role in neurodegeneration and/or neuroprotection depending on the CNS insult. However, all the above studies focused on the role of CX3CL1/CX3CR1 signaling in pathological conditions, ignoring the relevance of CX3CL1/CX3CR1 signaling under physiological conditions. No approach to date has been taken to decipher the significance of defects in CX3CL1/CX3CR1 signaling in physiological condition. In the present study we used CX3CR1⁻/⁻, CX3CR1⁺/⁻, and wild-type mice to investigate the physiological role of CX3CR1 receptor in cognition and synaptic plasticity. Our results demonstrate for the first time that mice lacking the CX3CR1 receptor show contextual fear conditioning and Morris water maze deficits. CX3CR1 deficiency also affects motor learning. Importantly, mice lacking the receptor have a significant impairment in long-term potentiation (LTP). Infusion with IL-1β receptor antagonist significantly reversed the deficit in cognitive function and impairment in LTP. Our results reveal that under physiological conditions, disruption in CX3CL1 signaling will lead to impairment in cognitive function and synaptic plasticity via increased action of IL-1β.
authors.affiliation: Department of Molecular Pharmacology and Physiology, USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida 33612, USA.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Rogers
authors.forename: Josh M
authors.initials: JM
authors.lastname: Morganti
authors.forename: Adam D
authors.initials: AD
authors.lastname: Bachstetter
authors.forename: Charles E
authors.initials: CE
authors.lastname: Hudson
authors.forename: Melinda M
authors.initials: MM
authors.lastname: Peters
authors.forename: Bethany A
authors.initials: BA
authors.lastname: Grimmig
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Weeber
authors.forename: Paula C
authors.initials: PC
authors.lastname: Bickford
authors.forename: Carmelina
authors.initials: C
authors.lastname: Gemma
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001703:Biophysics; D001973:Bromodeoxyuridine / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D003072:Cognition Disorders / Q000235:genetics / Q000473:pathology*; D003213:Conditioning, Psychological / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology*; D066298:In Vitro Techniques; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000235:genetics* / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D017628:Microglia / Q000473:pathology; D009043:Motor Activity / Q000235:genetics; D055495:Neurogenesis / Q000235:genetics; D018408:Patch-Clamp Techniques; D023062:Receptors, Interleukin-8A / Q000172:deficiency*; D045442:Rotarod Performance Test
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D008840:Microfilament Proteins; D023062:Receptors, Interleukin-8A; D001973:Bromodeoxyuridine
references.citation: J Clin Invest. 1997 Dec 1;100(11):2648-52
references.pmid: 9389726
references.citation: J Immunol. 1987 Jul 15;139(2):459-63
references.pmid: 2955042
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10896-901
references.pmid: 9724801
references.citation: Am J Pathol. 2010 Nov;177(5):2549-62
references.pmid: 20864679
references.citation: Nat Neurosci. 2006 Jul;9(7):917-24
references.pmid: 16732273
references.citation: Trends Neurosci. 2007 Nov;30(11):596-602
references.pmid: 17950926
references.citation: Mol Neurodegener. 2006 Sep 19;1:12
references.pmid: 16984644
references.citation: Endocrinology. 1990 Dec;127(6):3070-8
references.pmid: 2147409
references.citation: Physiol Behav. 2001 Aug;73(5):705-17
references.pmid: 11566205
references.citation: Cell. 1994 Sep 23;78(6):1027-37
references.pmid: 7923353
references.citation: Neuron. 2005 Aug 18;47(4):567-79
references.pmid: 16102539
references.citation: J Biol Chem. 1995 Mar 31;270(13):7420-6
references.pmid: 7535770
references.citation: Histol Histopathol. 2005 Jul;20(3):857-63
references.pmid: 15944936
references.citation: Glia. 2002 Jul;39(1):85-97
references.pmid: 12112378
references.citation: J Neurosci. 2007 Aug 1;27(31):8309-13
references.pmid: 17670977
references.citation: Nature. 1997 Feb 13;385(6617):640-4
references.pmid: 9024663
references.citation: Anat Rec. 1991 Dec;231(4):482-97
references.pmid: 1793176
references.citation: Neuron. 2010 Oct 6;68(1):19-31
references.pmid: 20920788
references.citation: Nat Neurosci. 2007 Nov;10(11):1387-94
references.pmid: 17965659
references.citation: J Neurosci. 2010 Dec 15;30(50):17091-101
references.pmid: 21159979
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11008-13
references.pmid: 8855299
references.citation: J Neurosci. 2002 Jul 15;22(14):5813-6
references.pmid: 12122042
references.citation: Int Rev Immunol. 1998;16(5-6):457-99
references.pmid: 9646173
references.citation: J Biol Chem. 2002 Oct 18;277(42):39944-52
references.pmid: 12167620
references.citation: J Neurosci. 1999 Mar 1;19(5):1708-16
references.pmid: 10024357
references.citation: Neurobiol Aging. 2011 Nov;32(11):2030-44
references.pmid: 20018408
references.citation: Curr Drug Targets Cardiovasc Haematol Disord. 2004 Mar;4(1):65-84
references.pmid: 15032653
references.citation: FEBS Lett. 1987 Nov 2;223(2):284-8
references.pmid: 2822487
references.citation: J Neurosci Res. 1997 Dec 15;50(6):1023-9
references.pmid: 9452017
references.citation: Int Rev Neurobiol. 2007;82:187-204
references.pmid: 17678962
references.citation: Cytokine Growth Factor Rev. 1997 Dec;8(4):253-65
references.pmid: 9620641
references.citation: Behav Brain Res. 1999 Dec;106(1-2):109-18
references.pmid: 10595426
references.citation: J Biol Chem. 2003 May 23;278(21):19453-62
references.pmid: 12609991
references.citation: J Biol Chem. 1993 Feb 25;268(6):4236-43
references.pmid: 8440707
references.citation: Neurosci Biobehav Rev. 2001 Jan;25(1):29-41
references.pmid: 11166076
references.citation: Neurobiol Learn Mem. 2002 Sep;78(2):379-89
references.pmid: 12431424
references.citation: Eur J Neurosci. 2005 Jan;21(1):1-14
references.pmid: 15654838
references.citation: Eur J Neurosci. 2004 Jan;19(2):234-46
references.pmid: 14725617
references.citation: Eur J Neurosci. 2007 Nov;26(10):2795-803
references.pmid: 18001276
references.citation: Neurosci Lett. 1996 Jan 12;203(1):17-20
references.pmid: 8742036
references.citation: Nat Neurosci. 2006 Dec;9(12):1512-9
references.pmid: 17115040
references.citation: Nat Neurosci. 2010 Apr;13(4):411-3
references.pmid: 20305648
references.citation: Glia. 2001 Nov;36(2):165-79
references.pmid: 11596125
references.citation: FASEB J. 2004 Aug;18(11):1297-9
references.pmid: 15208270