title: NMDA-receptor inhibition restores Protease-Activated Receptor 1 (PAR1) mediated alterations in homeostatic synaptic plasticity of denervated mouse dentate granule cells.
abstract: A common feature of neurological diseases is the loss of central neurons, which leads to deafferentation of connected brain regions. In turn, the remodeling of denervated neuronal networks is considered to play an important role for the postlesional recovery, but has also been linked to maladaptive plasticity resulting in disease-related complications such as memory dysfunction or epilepsy. Recent work has indicated that Protease-Activated Receptor 1 (PAR1), which can be activated by thrombin that enters the brain under pathological conditions, alters synaptic plasticity and neuronal excitability. However, the role of PAR1 in lesion-induced synaptic plasticity remains incompletely understood. Here, we used entorhinal denervation of organotypic hippocampal slice cultures to study the effects of PAR1 on denervation-induced homeostatic synaptic plasticity. Our results disclose that PAR1 activation counters the ability of denervated dentate granule cells to increase their excitatory synaptic strength in a compensatory, i.e., homeostatic manner. Furthermore, we demonstrate that this PAR1 effect is rescued by pharmacological inhibition of N-methyl-d-aspartate receptors (NMDA-R). Thus, NMDA-R inhibitors may restore the ability of denervated neurons to express homeostatic synaptic plasticity under conditions of increased PAR1-activity, which may contribute to their beneficial effects seen in the context of neurological diseases.
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Becker
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University Frankfurt, 60590 Frankfurt, Germany; Department of Neurology and Sagol Center for Neurosciences, Sheba Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, 52621 Tel Aviv, Israel.
authors.forename: Benno
authors.initials: B
authors.lastname: Ikenberg
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schiener
authors.affiliation: Department of Neurology and Sagol Center for Neurosciences, Sheba Medical Center, Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, 52621 Tel Aviv, Israel; Talpiot Medical Leadership Program, Department of Neurology and J. Sagol Neuroscience Center, The Chaim Sheba Medical Center, 52621 Tel HaShomer, Israel.
authors.forename: Nicola
authors.initials: N
authors.lastname: Maggio
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University Frankfurt, 60590 Frankfurt, Germany. Electronic address: a.vlachos@med.uni-frankfurt.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Vlachos
mesh_terms: D000818:Animals; D018891:Dentate Gyrus / Q000187:drug effects / Q000503:physiopathology*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques; D010975:Platelet Aggregation Inhibitors
chemical_list: D044463:Receptor, PAR-1; D016194:Receptors, N-Methyl-D-Aspartate; D010975:Platelet Aggregation Inhibitors
keywords: Blood coagulation; Brain injury; Neural homeostasis; SCH79797; SFLLRN; Synaptic scaling; Tetrodotoxin