title: Fractalkine/CX3CL1 enhances GABA synaptic activity at serotonin neurons in the rat dorsal raphe nucleus.
abstract: Serotonin (5-hydroxytryptamine; 5-HT) has an important role in mood regulation, and its dysfunction in the central nervous system (CNS) is associated with depression. Reports of mood and immune disorder co-morbidities indicate that immune-5-HT interactions may mediate depression present in immune compromised disease states including HIV/AIDS, multiple sclerosis, and Parkinson's disease. Chemokines, immune proteins that induce chemotaxis and cellular adhesion, and their G-protein coupled receptors distribute throughout the CNS, regulate neuronal patterning, and mediate neuropathology. The purpose of this study is to investigate the neuroanatomical and neurophysiological relationship between the chemokine fractalkine/CX3CL1 and its receptor CX3CR1 with 5-HT neurons in the rat midbrain raphe nuclei (RN). Immunohistochemistry was used to examine the colocalization of CX3CL1 or CX3CR1 with 5-HT in the RN, and whole-cell patch-clamp recordings in rat brain slices were used to determine the functional impact of CX3CL1 on 5-HT dorsal raphe nucleus (DRN) neurons. Greater than 70% of 5-HT neurons colocalize with CX3CL1 and CX3CR1 in the RN. CX3CL1 localizes as discrete puncta throughout the cytoplasm, whereas CX3CR1 concentrates to the perinuclear region of 5-HT neurons and exhibits microglial expression. CX3CL1 and CX3CR1 also colocalize with one another on individual RN cells. Electrophysiology studies indicate a CX3CL1-mediated enhancement of spontaneous inhibitory postsynaptic current (sIPSC) amplitude and dose-dependent increase of evoked IPSC (eIPSC) amplitude without affecting eIPSC paired-pulse ratio, a finding observed selectively in 5-HT neurons. CX3CL1's effect on eIPSC amplitude is blocked by pretreatment with an anti-CX3CL1 neutralizing antibody. Thus, CX3CL1 enhances postsynaptic GABA receptor number or sensitivity on 5-HT DRN neurons under conditions of both spontaneous and synaptically-evoked GABA release. CX3CL1 may indirectly inhibit 5-HT neurotransmission by increasing the sensitivity of 5-HT DRN neurons to GABA inputs. Therapies targeting CX3CL1 may treat serotonin related mood disorders, including depression experienced by patients with compromised immune systems.
authors.affiliation: Department of Anatomy and Cell Biology, Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: S
authors.initials: S
authors.lastname: Heinisch
authors.forename: L G
authors.initials: LG
authors.lastname: Kirby
mesh_terms: D000818:Animals; D054428:Chemokine CX3CL1 / Q000378:metabolism* / Q000494:pharmacology; D003866:Depressive Disorder / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D007154:Immune System Diseases / Q000150:complications / Q000503:physiopathology / Q000523:psychology; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000378:metabolism*; D009433:Neural Inhibition / Q000187:drug effects / Q000276:immunology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011903:Raphe Nuclei / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D054428:Chemokine CX3CL1; C515540:Cx3cl1 protein, rat; D012701:Serotonin; D005680:gamma-Aminobutyric Acid