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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.

Although memory impairments are a hallmark of aging, the degree of deficit varies across animal models, and is likely to reflect different states of deterioration in metabolic and endocrinological properties. This study investigated memory-related processes in young (3–4 months) and old (24 months) Sprague–Dawley rats (SD), which develop age-linked pathologies such as obesity or insulin-resistance and Lou/C/Jall rats, which do not develop such impairments. In short- and long-term memory recognition tasks, old Lou/C/Jall rats were never impaired whereas old SD rats were deficient at 1 and 24 h latencies. The expression of N-methyl-d-aspartate receptors (NMDAR)-mediated synaptic plasticity in CA1 hippocampal networks shifted towards lower activity values in old Lou/C/Jall rats whereas long-term potentiation was impaired in age-matched SD rats. Age-related decrease in NR2A subunits occurred in both strains, extended to NR2B, NR1 and GluR1 subunits in older animals (28 months) but only in SD rats. Therefore, the Lou/C/Jall rats can be considered as a model of healthy aging, not only in terms of its preserved metabolism, but also in terms of cognition and synaptic plasticity.

Activation of N-methyl-D-aspartate receptors (NMDARs) is the first step in the induction of certain forms of synaptic plasticity in the hippocampus. In the adult rat hippocampus, NMDARs are composed almost exclusively of NR1 and NR2 subunits with NR1 subunits being mainly associated with either NR2A and/or NR2B subunits. The role played by the different subunits in synaptic plasticity is still controversial. In the present study, we used two different long term depression (LTD) -inducing protocols (electrical and chemical stimulation) to show that activation of NR2A-containing NMDAR subunits leads to the induction of LTD. We also demonstrated that extrasynaptic NR2B-containing NMDARs regulate the magnitude of LTD by exerting a control over the function of synaptic NR2A-containing NMDARs while having no effect on plasticity in the absence of synaptic receptor activation. Taken as a whole, these experiments demonstrate that NMDAR subunits play different roles according to their nature (NR2A or NR2B) and location (synaptic versus extrasynaptic). This sheds new light on the functional role of extrasynaptic NR2B containing-NMDARs. These results are particularly important for a better understanding of certain pathological disorders associated with glutamatergic overactivity.