Pharmacological Modulation of Three Modalities of CA1 Hippocampal Long-Term Potentiation in the Ts65Dn Mouse Model of Down Syndrome.

Jonah J Scott-Mckean,Adriano L Roque,Witold K Surewicz,Mark W Johnson,Alberto C S Costa,Krystyna Surewicz

doi:10.1155/2018/9235796

Jonah J Scott-Mckean, Adriano L Roque + Show 4 more

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https://doi.org/10.1155/2018/9235796

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Journal: Neural plasticity	Publication Date: Jan 1, 2018
Citations: 12	License type: CC BY 4.0

Affiliation: Case Western Reserve University

Abstract

The Ts65Dn mouse is the most studied animal model of Down syndrome. Past research has shown a significant reduction in CA1 hippocampal long-term potentiation (LTP) induced by theta-burst stimulation (TBS), but not in LTP induced by high-frequency stimulation (HFS), in slices from Ts65Dn mice compared with euploid mouse-derived slices. Additionally, therapeutically relevant doses of the drug memantine were shown to rescue learning and memory deficits in Ts65Dn mice. Here, we observed that 1 μM memantine had no detectable effect on HFS-induced LTP in either Ts65Dn- or control-derived slices, but it rescued TBS-induced LTP in Ts65Dn-derived slices to control euploid levels. Then, we assessed LTP induced by four HFS (4xHFS) and found that this form of LTP was significantly depressed in Ts65Dn slices when compared with LTP in euploid control slices. Memantine, however, did not rescue this phenotype. Because 4xHFS-induced LTP had not yet been characterized in Ts65Dn mice, we also investigated the effects of picrotoxin, amyloid beta oligomers, and soluble recombinant human prion protein (rPrP) on this form of LTP. Whereas ≥10 μM picrotoxin increased LTP to control levels, it also caused seizure-like oscillations. Neither amyloid beta oligomers nor rPrP had any effect on 4xHFS-induced LTP in Ts65Dn-derived slices.

Highlights

Down syndrome (DS) is the set of phenotypic features of variable expressivity that results from an extra copy of chromosome 21 and is the most common genetically defined cause of intellectual disability [1, 2]
Memantine at a concentration of 1 μM had no effect on L-long-term potentiation (LTP) in control-derived slices, at 3 and 10 μM, it started to inhibit this form of LTP in slices from euploid mice
At therapeutic levels, memantine produces no adverse effects on the induction or maintenance of LTP in hippocampal slices from Ts65Dn mice and enhances the levels of one modality of LTP in slices from this mouse model of DS

Summary

Introduction

Down syndrome (DS) is the set of phenotypic features of variable expressivity that results from an extra copy of chromosome 21 (trisomy 21) and is the most common genetically defined cause of intellectual disability [1, 2]. Persons with DS typically display moderate intellectual disability [3], with disproportionate deficits in hippocampus-dependent and executive functions [4,5,6]. In attempts to understand the neurobiological basis for the cognitive deficits associated with DS, much emphasis has been placed on the study of synaptic plasticity in these animals, mostly long-term potentiation (LTP), and, to a smaller extent, long-term depression (LTD). This is because these forms of synaptic plasticity are thought to engage some of the major cellular and circuitlevel mechanisms underlying learning and memory [11, 12]

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