PMID- 28751018 OWN - NLM STAT- MEDLINE DCOM- 20180606 LR - 20220129 IS - 1090-2139 (Electronic) IS - 0889-1591 (Print) IS - 0889-1591 (Linking) VI - 66 DP - 2017 Nov TI - Deletion of the P2X4 receptor is neuroprotective acutely, but induces a depressive phenotype during recovery from ischemic stroke. PG - 302-312 LID - S0889-1591(17)30384-7 [pii] LID - 10.1016/j.bbi.2017.07.155 [doi] AB - INTRODUCTION: Acute ischemic injury leads to severe neuronal loss. One of the key mechanisms responsible for this effect is inflammation, which is characterized by the activation of myeloid cells, including resident microglia and infiltrating monocytes/macrophages. P2X4 receptors (P2X4Rs) present on these immune cells modulate the inflammatory response. For example, excessive release of adenosine triphosphate during acute ischemic stroke triggers stimulation of P2X4Rs, leading to myeloid cell activation and proliferation and further exacerbating post-ischemic inflammation. In contrast, during recovery P2X4Rs activation on microglia leads to the release of brain-derived neurotrophic factor (BDNF), which alleviate depression, maintain synaptic plasticity and hasten post-stroke behavioral recovery. Therefore, we hypothesized that deletion of the P2X4R specifically from myeloid cells would have differential effects on acute versus chronic recovery following stroke. METHODS: We subjected global or myeloid-specific (MS) P2X4R knock-out (KO) mice and wild-type littermates of both sexes to right middle cerebral artery occlusion (60min). We performed histological, behavioral (sensorimotor and depressive), and biochemical (quantitative PCR and flow cytometry) analyses to determine the acute (three days after occlusion) and chronic (30days after occlusion) effects of receptor deletion. RESULTS: Global P2X4R deletion led to reduced infarct size in both sexes. In MS P2X4R KO mice, only females showed reduced infarct size, an effect that did not change with ovariectomy. MS P2X4R KO mice of both sexes showed swift recovery from sensorimotor deficits during acute recovery but exhibited a more pronounced post-stroke depressive behavior phenotype that was independent of infarct size. Quantitative PCR analysis of whole cell lysate as well as flow-sorted myeloid cells from the perilesional cortex showed increased cellular interleukin 1 beta (IL-1beta), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) mRNA levels but reduced plasma levels of these cytokines in MS P2X4R KO mice after stroke. The expression levels of BDNF and other depression-associated genes were reduced in MS P2X4R KO mice after stroke. CONCLUSIONS: P2X4R deletion protects against stroke acutely but predisposes to depression-like behavior chronically after stroke. Thus, a time-sensitive approach should be considered when targeting P2X4Rs after stroke. CI - Copyright (c) 2017 Elsevier Inc. All rights reserved. FAU - Verma, Rajkumar AU - Verma R AD - Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06032, USA; Calhoun Cardiology Center, University of Connecticut Health Center, Farmington, CT 06032, USA. Electronic address: raverma@uchc.edu. FAU - Cronin, Chunxia G AU - Cronin CG AD - Calhoun Cardiology Center, University of Connecticut Health Center, Farmington, CT 06032, USA. FAU - Hudobenko, Jacob AU - Hudobenko J AD - Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06032, USA; Department of Neurology, McGovern Medical School University of Texas, Houston, TX 77030, USA. FAU - Venna, Venugopal R AU - Venna VR AD - Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06032, USA; Department of Neurology, McGovern Medical School University of Texas, Houston, TX 77030, USA. FAU - McCullough, Louise D AU - McCullough LD AD - Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06032, USA; Department of Neurology, McGovern Medical School University of Texas, Houston, TX 77030, USA. FAU - Liang, Bruce T AU - Liang BT AD - Calhoun Cardiology Center, University of Connecticut Health Center, Farmington, CT 06032, USA. LA - eng GR - 14POST20380612/AHA_/American Heart Association-American Stroke Association/United States GR - R01 HL048225/HL/NHLBI NIH HHS/United States GR - R01 NS055215/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20170724 PL - Netherlands TA - Brain Behav Immun JT - Brain, behavior, and immunity JID - 8800478 RN - 0 (Cytokines) RN - 0 (Inflammation Mediators) RN - 0 (RNA, Messenger) RN - 0 (Receptors, Purinergic P2X4) SB - IM MH - Animals MH - Behavior, Animal MH - Brain/*metabolism/pathology MH - Brain Ischemia/complications/*metabolism/*pathology MH - Cytokines/metabolism MH - Depression/*complications/genetics MH - Female MH - Inflammation Mediators/metabolism MH - Male MH - Mice MH - Mice, Knockout MH - Microglia/pathology MH - Phenotype MH - RNA, Messenger/metabolism MH - Receptors, Purinergic P2X4/genetics/metabolism/*physiology MH - Recovery of Function MH - Stroke/complications/*metabolism/*pathology PMC - PMC5650951 MID - NIHMS896391 OTO - NOTNLM OT - Depression OT - Myeloid-specific OT - Neuroprotection OT - P2X4R OT - Stroke COIS- Conflict(s)-of-Interest/Disclosure(s) None declared. EDAT- 2017/07/29 06:00 MHDA- 2018/06/07 06:00 PMCR- 2018/11/01 CRDT- 2017/07/29 06:00 PHST- 2017/04/12 00:00 [received] PHST- 2017/07/23 00:00 [revised] PHST- 2017/07/23 00:00 [accepted] PHST- 2017/07/29 06:00 [pubmed] PHST- 2018/06/07 06:00 [medline] PHST- 2017/07/29 06:00 [entrez] PHST- 2018/11/01 00:00 [pmc-release] AID - S0889-1591(17)30384-7 [pii] AID - 10.1016/j.bbi.2017.07.155 [doi] PST - ppublish SO - Brain Behav Immun. 2017 Nov;66:302-312. doi: 10.1016/j.bbi.2017.07.155. Epub 2017 Jul 24.