Neuraminidase inhibition primes short-term depression and suppresses long-term potentiation of synaptic transmission in the rat hippocampus.

Alina Savotchenko,Vadym Sydorenko,Dmytro Isaev,Gregory L. Holmes,Arthur Romanov,Oleksandr Maximyuk,Elena Isaeva

doi:10.1155/2015/908190

Abstract

Neuraminidase (NEU) is a key enzyme that cleaves negatively charged sialic acid residues from membrane proteins and lipids. Clinical and basic science studies have shown that an imbalance in NEU metabolism or changes in NEU activity due to various pathological conditions parallel with behavior and cognitive impairment. It has been suggested that the decreases of NEU activity could cause serious neurological consequences. However, there is a lack of direct evidences that modulation of endogenous NEU activity can impair neuronal function. Using combined rat entorhinal cortex/hippocampal slices and a specific inhibitor of NEU, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (NADNA), we examined the effect of downregulation of NEU activity on different forms of synaptic plasticity in the hippocampal CA3-to-CA1 network. We show that NEU inhibition results in a significant decrease in long-term potentiation (LTP) and an increase in short-term depression. Synaptic depotentiation restores LTP in NADNA-pretreated slices to the control level. These data suggest that short-term NEU inhibition produces the LTP-like effect on neuronal network, which results in damping of further LTP induction. Our findings demonstrate that downregulation of NEU activity could have a major impact on synaptic plasticity and provide a new insight into the cellular mechanism underlying behavioral and cognitive impairment associated with abnormal metabolism of NEU.

Highlights

Long chains of negatively charged sialic acid occupy a prominent position on cellular membrane proteins in complex carbohydrates, which are major constituents of membrane proteins and lipids and are involved in manifold cell signaling events [1]
As the deficit of NEU activity is associated with behavior and mental impairment and alterations of the level of polysialic acid (PSA) and neuronal network activity alter synaptic plasticity, we examined the consequences of NEU inhibition on synaptic plasticity as a cellular basis for behavioral and cognitive functions
Input/output curves revealed a significant increase of the maximal rising slope of field excitatory postsynaptic potential (fEPSP) in NADNA-pretreated slices compared to controls (NADNApretreated group: 0.20 ± 0.05 mV/ms [n = 21]; control: 0.08 ± 0.02 mV/ms [n = 17], t36 = 2.1, P < 0.05, Figure 1(b)(b2)) without alteration of Fiber volley (FV) amplitude (NADNA-pretreated group: 0.22 ± 0.01 mV [n = 11]; control: 0.20 ± 0.01 mV [n = 17], t19 = 0.9, P = 0.34, Figure 1(b)(b1))

Summary

Introduction

Long chains of negatively charged sialic acid occupy a prominent position on cellular membrane proteins in complex carbohydrates, which are major constituents of membrane proteins and lipids and are involved in manifold cell signaling events [1]. In the central nervous system, sialic acids play an important role in many processes such as neurogenesis, cell differentiation, migration, axon sprouting, synaptogenesis, plasticity, and neuronal excitability [2, 3]. The physiological role of sialic acid comes from studies using neuraminidase (NEU) as an enzyme, which hydrolyzes terminal sialic acid residues from cellular glycoconjugates. Mental retardation and seizures are common clinical features of inherited disorders of defective or deficient NEU activity [13, 14]. Various pathological conditions such as chronic stress, seizure activity, and chronic ethanol treatment

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