title: Differential effects of P2Y1 deletion on glial activation and survival of photoreceptors and amacrine cells in the ischemic mouse retina.
abstract: Gliosis of retinal Müller glial cells may have both beneficial and detrimental effects on neurons. To investigate the role of purinergic signaling in ischemia-induced reactive gliosis, transient retinal ischemia was evoked by elevation of the intraocular pressure in wild-type (Wt) mice and in mice deficient in the glia-specific nucleotide receptor P2Y1 (P2Y1 receptor-deficient (P2Y1R-KO)). While control retinae of P2Y1R-KO mice displayed reduced cell numbers in the ganglion cell and inner nuclear layers, ischemia induced apoptotic death of cells in all retinal layers in both, Wt and P2Y1R-KO mice, but the damage especially on photoreceptors was more pronounced in retinae of P2Y1R-KO mice. In contrast, gene expression profiling and histological data suggest an increased survival of amacrine cells in the postischemic retina of P2Y1R-KO mice. Interestingly, measuring the ischemia-induced downregulation of inwardly rectifying potassium channel (Kir)-mediated K(+) currents as an indicator, reactive Müller cell gliosis was found to be weaker in P2Y1R-KO (current amplitude decreased by 18%) than in Wt mice (decrease by 68%). The inner retina harbors those neurons generating action potentials, which strongly rely on an intact ion homeostasis. This may explain why especially these cells appear to benefit from the preserved Kir4.1 expression in Müller cells, which should allow them to keep up their function in the context of spatial buffering of potassium. Especially under ischemic conditions, maintenance of this Müller cell function may dampen cytotoxic neuronal hyperexcitation and subsequent neuronal cell loss. In sum, we found that purinergic signaling modulates the gliotic activation pattern of Müller glia and lack of P2Y1 has janus-faced effects. In the end, the differential effects of a disrupted P2Y1 signaling onto neuronal survival in the ischemic retina call the putative therapeutical use of P2Y1-antagonists into question.
authors: Paul-Flechsig-Institut für Hirnforschung, Universität Leipzig, Leipzig, Germany.
authors: T
authors: T
authors: Pannicke
authors: Paul-Flechsig-Institut für Hirnforschung, Universität Leipzig, Leipzig, Germany.
authors: I
authors: I
authors: Frommherz
authors: Paul-Flechsig-Institut für Hirnforschung, Universität Leipzig, Leipzig, Germany.
authors: B
authors: B
authors: Biedermann
authors: Paul-Flechsig-Institut für Hirnforschung, Universität Leipzig, Leipzig, Germany.
authors: L
authors: L
authors: Wagner
authors: Paul-Flechsig-Institut für Hirnforschung, Universität Leipzig, Leipzig, Germany.
authors: K
authors: K
authors: Sauer
authors: 1] Paul-Flechsig-Institut für Hirnforschung, Universität Leipzig, Leipzig, Germany [2] Biotechnology Center, Technische Universität Dresden, Dresden, Germany.
authors: E
authors: E
authors: Ulbricht
authors: Paul-Flechsig-Institut für Hirnforschung, Universität Leipzig, Leipzig, Germany.
authors: W
authors: W
authors: Härtig
authors: Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Universität Leipzig, Leipzig, Germany.
authors: U
authors: U
authors: Krügel
authors: Paul-Flechsig-Institut für Hirnforschung, Universität Leipzig, Leipzig, Germany.
authors: U
authors: U
authors: Ueberham
authors: Paul-Flechsig-Institut für Hirnforschung, Universität Leipzig, Leipzig, Germany.
authors: T
authors: T
authors: Arendt
authors: Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Universität Leipzig, Leipzig, Germany.
authors: P
authors: P
authors: Illes
authors: Klinik und Poliklinik für Augenheilkunde, Universität Leipzig, Leipzig, Germany.
authors: A
authors: A
authors: Bringmann
authors: Paul-Flechsig-Institut für Hirnforschung, Universität Leipzig, Leipzig, Germany.
authors: A
authors: A
authors: Reichenbach
authors: 1] Paul-Flechsig-Institut für Hirnforschung, Universität Leipzig, Leipzig, Germany [2] Institut für Humangenetik, Universität Regensburg, Regensburg, Germany.
authors: A
authors: A
authors: Grosche
mesh_terms: D025042:Amacrine Cells / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D004195:Disease Models, Animal; D063928:Ependymoglial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007511:Ischemia / Q000150:complications*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D020419:Photoreceptor Cells, Vertebrate / Q000166:cytology* / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1 / Q000235:genetics* / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000378:metabolism; D012164:Retinal Diseases / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D058472:Receptors, Purinergic P2Y1