Abstract

Protease activated receptor-1 (PAR1) is expressed in multiple cell types in the CNS, with the most prominent expression in glial cells. PAR1 activation enhances excitatory synaptic transmission secondary to the release of glutamate from astrocytes following activation of astrocytically-expressed PAR1. In addition, PAR1 activation exacerbates neuronal damage in multiple in vivo models of brain injury in a manner that is dependent on NMDA receptors. In the hippocampal formation, PAR1 mRNA appears to be expressed by a subset of neurons, including granule cells in the dentate gyrus. In this study we investigate the role of PAR activation in controlling neuronal excitability of dentate granule cells. We confirm that PAR1 protein is expressed in neurons of the dentate cell body layer as well as in astrocytes throughout the dentate. Activation of PAR1 receptors by the selective peptide agonist TFLLR increased the intracellular Ca2+ concentration in a subset of acutely dissociated dentate neurons as well as non-neuronal cells. Bath application of TFLLR in acute hippocampal slices depolarized the dentate gyrus, including the hilar region in wild type but not in the PAR1-/- mice. PAR1 activation increased the frequency of action potential generation in a subset of dentate granule neurons; cells in which PAR1 activation triggered action potentials showed a significant depolarization. The activation of PAR1 by thrombin increased the amplitude of NMDA receptor-mediated component of EPSPs. These data suggest that activation of PAR1 during normal function or pathological conditions, such as during ischemia or hemorrhage, can increase the excitability of dentate granule cells.

Highlights

  • Protease activated receptor 1 (PAR1) is a G-protein coupled receptor that is best known for its role in coagulation and homeostasis [1,2,3]

  • We show that PAR1 activation leads to granule cell depolarization and potentiation of synaptically-activated NMDA receptor function

  • PAR1 expression in dentate granule cells Multiple studies indicate that PAR1 mRNA is expressed in both neurons and glia in a variety of brain regions [11,12]

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Summary

Introduction

Protease activated receptor 1 (PAR1) is a G-protein coupled receptor that is best known for its role in coagulation and homeostasis [1,2,3]. PAR-1 is activated when serine proteases such as thrombin or plasmin cleave the N-terminus at Arg, revealing a new N-terminus that acts as a tethered ligand to activate receptor signaling [4,5]. PAR-1 signals through multiple G-proteins, including Gi, Gq, and G12/13 [5,6,7], and is highly expressed in astrocytes throughout the CNS [8,9,10], and differentially expressed in neuronal subpopulations in discrete regions, including granule cell layer of dentate gyrus [8,11,12].

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