Serine/Threonine Phosphatases in LTP: Two B or Not to Be the Protein Synthesis Blocker-Induced Impairment of Early Phase.

Alexander V Maltsev,Pavel M Balaban,Natalia V Bal

doi:10.3390/ijms22094857

Alexander V Maltsev, Pavel M Balaban + Show 1 more

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https://doi.org/10.3390/ijms22094857

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Abstract

Dephosphorylation of target proteins at serine/threonine residues is one of the most crucial mechanisms regulating their activity and, consequently, the cellular functions. The role of phosphatases in synaptic plasticity, especially in long-term depression or depotentiation, has been reported. We studied serine/threonine phosphatase activity during the protein synthesis blocker (PSB)-induced impairment of long-term potentiation (LTP). Established protein phosphatase 2B (PP2B, calcineurin) inhibitor cyclosporin A prevented the LTP early phase (E-LTP) decline produced by pretreatment of hippocampal slices with cycloheximide or anisomycin. For the first time, we directly measured serine/threonine phosphatase activity during E-LTP, and its significant increase in PSB-treated slices was demonstrated. Nitric oxide (NO) donor SNAP also heightened phosphatase activity in the same manner as PSB, and simultaneous application of anisomycin + SNAP had no synergistic effect. Direct measurement of the NO production in hippocampal slices by the NO-specific fluorescent probe DAF-FM revealed that PSBs strongly stimulate the NO concentration in all studied brain areas: CA1, CA3, and dentate gyrus (DG). Cyclosporin A fully abolished the PSB-induced NO production in the hippocampus, suggesting a close relationship between nNOS and PP2B activity. Surprisingly, cyclosporin A alone impaired short-term plasticity in CA1 by decreasing paired-pulse facilitation, which suggests bi-directionality of the influences of PP2B in the hippocampus. In conclusion, we proposed a minimal model of signaling events that occur during LTP induction in normal conditions and the PSB-treated slices.

Highlights

Long-term potentiation (LTP), long-term depression (LTD), and depotentiation are the key forms of synaptic plasticity at different brain regions: amygdala, hippocampus, cerebellum, etc. [1,2,3]
We investigated the relationship between Nitric oxide (NO)-dependent suppression of LTP caused by the application of the protein synthesis blockers (PSBs) and PP2B
Direct measurements of serine/threonine phosphatase activity in hippocampal slices in our experiments showed that the PSB applications lead to its substantial increase, which is inhibited in the presence of cyclosporin A

Summary

Introduction

Long-term potentiation (LTP), long-term depression (LTD), and depotentiation are the key forms of synaptic plasticity at different brain regions: amygdala, hippocampus, cerebellum, etc. [1,2,3]. Long-term potentiation (LTP), long-term depression (LTD), and depotentiation are the key forms of synaptic plasticity at different brain regions: amygdala, hippocampus, cerebellum, etc. The LTP phenomenon, consisting of the strengthening of synaptic transmission between pre- and postsynaptic neurons due to high-frequency stimulation of afferent pathway, is the most studied form of plasticity [7,8,9]. It is conditionally divided into an early phase (E-LTP), which is protein synthesis-independent and lasts from tens of minutes to several hours, and a late phase (L-LTP), which is protein synthesis-dependent and persists for many hours [10]. L-LTP is to a certain extent supported by kinases activated during

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