NMDA-receptor inhibition restores Protease-Activated Receptor 1 (PAR1) mediated alterations in homeostatic synaptic plasticity of denervated mouse dentate granule cells.
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.
['Becker|Denise|D|', 'Ikenberg|Benno|B|', 'Schiener|Sabine|S|', 'Maggio|Nicola|N|', 'Vlachos|Andreas|A|']
D000818:Animals D018891:Dentate Gyrus D006706:Homeostasis D008810:Mice, Inbred C57BL D018345:Mice, Knockout D009473:Neuronal Plasticity D009474:Neurons D044463:Receptor, PAR-1 D016194:Receptors, N-Methyl-D-Aspartate D013569:Synapses D009435:Synaptic Transmission D046509:Tissue Culture Techniques
Blood coagulation Brain injury Neural homeostasis SCH79797 SFLLRN Synaptic scaling Tetrodotoxin