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. 2013 Jan;124(1):109-22.
doi: 10.1111/jnc.12075. Epub 2012 Nov 21.

Protease-activated receptor-1 modulates hippocampal memory formation and synaptic plasticity

Antoine G Almonte  1 , Laura H Qadri, Faraz A Sultan, Jennifer A Watson, Daniel J Mount, Gavin Rumbaugh, J David Sweatt
Affiliations

Protease-activated receptor-1 modulates hippocampal memory formation and synaptic plasticity

Antoine G Almonte et al. J Neurochem. 2013 Jan.

Abstract

Protease-activated receptor-1 (PAR1) is an unusual G-protein coupled receptor (GPCR) that is activated through proteolytic cleavage by extracellular serine proteases. Although previous work has shown that inhibiting PAR1 activation is neuroprotective in models of ischemia, traumatic injury, and neurotoxicity, surprisingly little is known about PAR1's contribution to normal brain function. Here, we used PAR1-/- mice to investigate the contribution of PAR1 function to memory formation and synaptic function. We demonstrate that PAR1-/- mice have deficits in hippocampus-dependent memory. We also show that while PAR1-/- mice have normal baseline synaptic transmission at Schaffer collateral-CA1 synapses, they exhibit severe deficits in N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP). Mounting evidence indicates that activation of PAR1 leads to potentiation of NMDAR-mediated responses in CA1 pyramidal cells. Taken together, this evidence and our data suggest an important role for PAR1 function in NMDAR-dependent processes subserving memory formation and synaptic plasticity.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. PAR1 −/− mice show significant impairments in contextual fear conditioning
(A) PAR1 −/− mice show similar freezing behavior after each foot-shock as wild-type mice during training. (B) PAR1 −/− mice show significantly less freezing behavior on the test day (n=9 mice per genotype, PAR1 +/+: 70.48 ± 3.77, PAR1 −/−: 56.05 ± 4.23). Data are presented as mean ± SEM.
Figure 2
Figure 2. Loss of PAR1 function does not alter hippocampal morphology
(A) There are no gross abnormalities in hippocampal morphology as visualized by cresyl violet staining between PAR1+/+ and PAR1 −/− mice. Scale bar: 0.5 mm. (B) PAR1 mRNA expression is present in tissue from PAR1 +/+ (WT) hippocampus (HC) and cortex (CX). There are no detectable levels of PAR1 mRNA in either hippocampal or cortical tissue from PAR1 −/− (KO) mice. (C) In WT mice, PAR1 gene expression is highly enriched in cortex, hippocampus and cerebellum (n=3 brains from WT mice; cortex: 1 ± 0.173, hippocampus: 6.91 ± 0.714, cerebellum: 6.63 ± 0.895). Data are normalized to cortex and presented as mean ± SEM.
Figure 3
Figure 3. PAR1 −/− mice have normal baseline synaptic transmission and paired-pulse facilitation at Schaffer collateral-CA1 synapses
PAR1 −/− mice display comparable baseline synaptic transmission as wild-type mice, as measured by (A–C) input-output curves (PAR1 +/+: n=25 slices from 8 mice; PAR1 −/−: n=25 slices from 7 mice). (D) PAR1 −/− mice also display normal short-term plasticity at these synapses as measured by paired-pulse facilitation (PAR1 +/+: n=11 slices from 4 mice; PAR1 −/−: n=9 slices from 4 mice). Data are presented as mean ± SEM.
Figure 4
Figure 4. Loss of PAR1 function results in impaired synaptic plasticity at Schaffer collateral-CA1 synapses
(A) PAR1 −/− mice display significantly decreased levels of LTP after induction by theta-burst stimulation (TBS; PAR1 +/+: n=8 slices from 5 mice; PAR1−/−: n=7 slices from 4 mice; #=PAR1 −/− vs. 1.0, p<0.001). LTP magnitudes, measured by averaging normalized fEPSP slopes for the last 10 minutes of recording were: PAR1 +/+: 1.56 ± 0.01, and PAR1 −/−: 1.17 ± 0.01. Insets show representative traces before and after LTP induction. Scale bars: 0.2 mV, 20 ms. (B) PAR1 −/− mice show comparable levels of PTP, but also show significantly less potentiation at 20, 60, and 120 minutes post-TBS. (C, D) PAR1 −/− mice have impaired synaptic responses during TBS. The areas of the composite responses produced by each theta burst within the train were measured. Areas of Bursts 2–10 were then divided by the area of the initial theta burst to produce a relative area. (C) Representative traces for bursts 1, 4, and 10. PAR1 +/+: black traces, PAR1 −/−: gray traces. Scale bars: 0.5 mV, 15 ms. Data are presented as mean ± SEM. (E) fEPSP areas and decay times of synaptic responses at 50% of the threshold for eliciting population spikes were not significantly different between wild-type and PAR1 −/− mice (PAR1 +/+: n=27 slices from 9 mice, PAR1 −/−: n=27 slices from 8 mice). Insets show representative traces from each genotype (PAR1 +/+: black trace, PAR1 −/−: gray trace). Scale bars: 0.5 mV, 20 ms.
Figure 5
Figure 5. Loss of PAR1 function reduces the ceiling for LTP
(A) PAR1 −/− mice have significantly lower saturation levels for LTP (PAR1 +/+: n=3 slices from 3 mice; PAR1 −/−: n=3 slices from 3 mice). (B) PAR1 −/− mice display significantly lower levels of potentiation following each burst. LTP saturation levels were: PAR1 +/+: 2.39 ± 0.006, and PAR1−/−: 1.44 ± 0.002. (C) Peak PTP levels following each burst delivery were not significantly different between wild-type and PAR1 −/− mice.
Figure 6
Figure 6. Loss of PAR1 function impairs the induction and ceiling for NMDAR-dependent LTP, but does not impair NMDAR function or expression
(A) Lower saturation levels in PAR1 −/− mice persist under conditions favoring NMDAR activation (10 μM EDTA added to ACSF, 3 X TBS stimulation; PAR1 +/+: n=5 slices from 3 mice; PAR1 −/−: n=5 slices from 3 mice) Insets show representative traces before and after LTP induction. Scale bars: 0.2 mV, 20 ms. (B) PAR1 −/− mice show significantly less potentiation at 10, 20, 60, and 120 minutes post-TBS. (C) NMDAR-mediated synaptic responses are not impaired in PAR1−/− mice. Inset shows representative AMPAR-mediated response (gray trace) and NMDAR-mediated response (black trace) (PAR1 +/+: n=7 slices from 4 mice; PAR1 −/−: 7 slices from 3 mice). Scale bars: 0.5 mV, 20 ms. (D) AMPAR and NMDAR subunit expression levels are not significantly altered in PAR1 −/− hippocampal whole-cell lysates (n=6 animals per genotype).
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