The anticoagulant activated protein C (aPC) promotes metaplasticity in the hippocampus through an EPCR-PAR1-S1P1 receptors dependent mechanism

Abstract

Thrombin and other clotting factors regulate long-term potentiation (LTP) in the hippocampus through the activation of the protease activated receptor 1 (PAR1) and consequent potentiation of N-methyl-d-aspartate receptor (NMDAR) functions. We have recently shown that the activation of PAR1 either by thrombin or the anticoagulant factor activated protein C (aPC) has differential effects on LTP. While thrombin activation of PAR1 induces an NMDAR-mediated slow onset LTP, which saturates the ability to induce further LTP in the exposed network, aPC stimulation of PAR1 enhances tetanus induced LTP through a voltage-gated calcium channels mediated mechanism. In this study, we addressed the mechanisms by which aPC enhances LTP in hippocampal slices. Using extracellular recordings, we show that a short tetanic stimulation, which does not induce LTP, is able to enhance plasticity in the presence of aPC through a mechanism that requires the activation of sphingosine-1 phosphate receptor 1 and intracellular Ca(2+) stores. These data identify aPC as a "metaplastic molecule", capable of shifting the threshold of LTP towards further potentiation. Our findings propose novel strategies to enhance plasticity in neurological diseases associated with the breakdown of the blood brain barrier and alterations in synaptic plasticity.

Fingolimod for the treatment of neurological diseases—state of play and future perspectives

“…Interestingly, Maggio et al (2014) characterized aPC as a metaplastic molecule that enhances LTP upon delivery of a subthreshold stimulation. They propose a model in which upon binding to the endothelial protein C receptor, which is also expressed on astrocytes, aPC activates PAR1, which triggers the SphK-dependent production of S1P.…”

Novel pharmaceutical treatments for minimal traumatic brain injury and evaluation of animal models and methodologies supporting their development

“…Using rodent models of mTBI and relevant cognitive and biological tests, numerous treatments with mechanism-based drug features have been reported to ameliorate mTBI induced cognitive deficits. As a recent example among many, we have lately shown that an increased thrombin concentration induced by mTBI may cause amnesia through the activation of its receptor, the proteases activated receptor 1 (PAR1) (Itzekson et al, 2014, Maggio et al, 2014); thereby exposing a novel therapeutic target potentially underpinning cognitive detriments of trauma. In the following sections, several widely used rodent models of mTBI are highlighted that can be combined with well characterized behavioral assays, epitomized by the novel object recognition (NOR) task for assessing cognitive deficits, to provide a methodological toolbox for evaluating molecular mechanisms involved in mTBI.…”

“…Notably, PAR-1 knockout animals present with substantial impairments in hippocampus-dependent learning and memory processes (Almonte et al, 2007, 2013). In synopsis, PAR-1 has a key role in memory formation and synaptic plasticity (Maggio et al, 2013a,b, 2014), which can be regulated in a concentration-dependent manner by thrombin under physiological and pathological conditions. Interestingly, thrombin concentrations rise in the brain just a few minutes following a mTBI (Itzekson et al, 2014; Maggio et al, 2014), with such an increase in concentrations related to a poor NOR performance in animals challenged by brain trauma.…”

“…In synopsis, PAR-1 has a key role in memory formation and synaptic plasticity (Maggio et al, 2013a,b, 2014), which can be regulated in a concentration-dependent manner by thrombin under physiological and pathological conditions. Interestingly, thrombin concentrations rise in the brain just a few minutes following a mTBI (Itzekson et al, 2014; Maggio et al, 2014), with such an increase in concentrations related to a poor NOR performance in animals challenged by brain trauma. Notably, injection of the PAR1 antagonist SCH79797 prevents memory deficit and rescues LTP in injured mice.…”

Ablation of Sphingosine 1-Phosphate Receptor Subtype 3 Impairs Hippocampal Neuron Excitability In vitro and Spatial Working Memory In vivo

“…Pharmacological evidence suggests that S1P and S1P 3 are associated with LTP formation (Maggio et al, 2014). However, S1P significantly increased eEPSC amplitudes and eEPSC decay times both in WT and in ${\text{S1P}}_3^{-/-}$ mice, suggesting an increase in glutamate release, and possibly a reduction in non-NMDA receptor desensitization.…”