Partial inhibition of PP1 alters bidirectional synaptic plasticity in the hippocampus

Abstract

Synaptic plasticity is an important cellular mechanism that underlies memory formation. In brain areas involved in memory such as the hippocampus, long-term synaptic plasticity is bidirectional. Major forms of bidirectional plasticity encompass long-term potentiation (LTP), LTP reversal (depotentiation) and long-term depression (LTD). Protein kinases and protein phosphatases are important players in the induction of both LTP and LTD, and the serine/threonine protein phosphatase-1 (PP1), in particular, has emerged as a key phosphatase in these processes. The goal of the present study was to assess the contribution of PP1 to bidirectional plasticity and examine the impact of a partial inhibition of PP1 on LTP, LTD and depotentiation in the mouse hippocampus. For this, we used transgenic mice expressing an active PP1 inhibitor (I-1*) inducibly in forebrain neurons. We show that partial inhibition of PP1 by I-1* expression alters the properties of bidirectional plasticity by inducing a shift of synaptic responses towards potentiation. At low-frequency stimulation, PP1 inhibition decreases LTD in a frequency-dependent fashion. It favours potentiation over depression at intermediate frequencies and increases LTP at high frequency. Consistently, it also impairs depotentiation. These results indicate that the requirement of bidirectional plasticity for PP1 is frequency-dependent and that a broad range of plasticity is negatively constrained by PP1, a feature that may correlate with the property of PP1 to constrain learning efficacy and promote forgetting.

Aβ Oligomer-Mediated Long-Term Potentiation Impairment Involves Protein Phosphatase 1-Dependent Mechanisms

“…This may involve direct dephosphorylation of CaMKII by PP1, because CaMKII is a known target of PP1 (Strack et al, 1997) and could account for the alteration in plasticity in our model, which is severe, despite normal expression of NMDA and AMPA receptors and synaptophysin. Interestingly, PP1 inhibition in vivo has been shown to increase CaMKII phosphorylation, shift hippocampal plasticity toward potentiation (Jouvenceau et al, 2006), and reverse cognitive deficits in aged mice (Genoux et al, 2002). The present results significantly extend these previous findings by demonstrating the relevance of these PP1-dependent pathways in the mechanisms of AD.…”

“…Plasticity was then induced by stimulation with either 1 Hz for 15 min (900 pulses), 2 Hz for 10 min (1200 pulses), 5 Hz for 3 min (900 pulses), 10 Hz for 1.5 min (900 pulses), or 100 Hz for three trains of 1 s tetanus separated by 20 s. Data were analyzed by measuring the slope of individual fEPSPs at 1-1.5 ms after the stimulus pulse by linear fitting using Clampfit (Molecular Devices). The frequency-dependent plasticity curve (BCM curve) was built by determining mean fEPSP slopes over 10 min starting 35 min after stimulation (according to Jouvenceau et al, 2006).…”

“…Because PP1 is a major protein phosphatase in neurons that negatively regulates intracellular signaling downstream from the NMDA receptor (including CaMKII) and modulates hippocampal LTP (Jouvenceau et al, 2006;Mansuy and Shenolikar, 2006), we examined whether it might be involved in the deficit in plasticity induced by A␤ oligomers. PP1 was inhibited pharmacologically in acute hippocampal slices from arcA␤ mice and wild-type littermates using the selective inhibitor tautomycin (1 nM), and the effect on plasticity was examined across several stimulation frequencies.…”

Protein Phosphatase 1 Regulates the Histone Code for Long-Term Memory

“…Further to revealing a hitherto-unknown role for PP1 in neuronal cells, the data show that nuclear PP1 has distinct functions from synaptic PP1 (Hu et al, 2006;Jouvenceau et al, 2006;Mansuy and Shenolikar, 2006) and underscore the importance of PP1 in multiple fundamental cellular processes and of its subcellular compartmentalization (Virshup and Shenolikar, 2009). These results significantly extend recent reports showing that the protein kinases MSK1, ERK/MAPK, and IB are involved in the control of histone PTMs in memory (Levenson et al, 2004;Chwang et al, 2006Chwang et al, , 2007Lubin and Sweatt, 2007) and suggest that PP1 is the primary PP that counteracts these kinases.…”

Differential Regulation of AMPA Receptor Trafficking by Neurabin-Targeted Synaptic Protein Phosphatase-1 in Synaptic Transmission and Long-Term Depression in Hippocampus

“…Besides protein phosphatase-1 (PP1) enzymatic activity, PP1 synaptic targeting is critical for the induction and maintenance of long-term depression (LTD) in hippocampus (Mulkey et al, 1993;Morishita et al, 2001;Hu et al, 2006;Jouvenceau et al, 2006). PP1 targeting proteins direct PP1 to the immediate vicinity of PP1 substrates for specific and efficient catalysis.…”