Activation of Protease Activated Receptor 1 Increases the Excitability of the Dentate Granule Neurons of Hippocampus
- Activation of Protease Activated Receptor 1 Increases the Excitability of the Dentate Granule Neurons of Hippocampus
- 한경석; Guido Mannaioni; Cecily E. Hamill; 이재광; Candice E. Junge; 이창준; Stephen F. Traynelis
- Issue Date
- Molecular Brain
- VOL 4, 32-1-32-12
- 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 nonneuronal
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.
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