Regulation of structural and functional synapse density by L-threonate through modulation of intraneuronal magnesium concentration

NEUROPHARMACOLOGY

卷:108

Article

Sun, Qifeng¹  Weinger, Jason G.²  Mao, Fei²  Liu, Guosong^1,2 

[1] Tsinghua Univ, Sch Med, Beijing 100084, Peoples R China

[2] Neurocentria Inc, Fremont, CA 94538 USA

关键词: Threonate;    Synaptic density;    Functional terminals;    Intracellular Mg2+;    Rat;    Human stem cell -derived neurons;   

DOI  :  10.1016/j.neuropharm.2016.05.006

来源: Elsevier

【 摘 要 】

Oral administration of the combination of L-threonate (threonate) and magnesium (Mg2+) in the form of L-Threonic acid Magnesium salt (L-TAMS) can enhance learning and memory in young rats and prevent memory decline in aging rats and in Alzheimer's disease model mice. Recent results from a human clinical trial demonstrate the efficacy of L-TAMS in restoring global cognitive abilities of older adults. Previously, we reported that neuronal intracellular Mg2+ serves as a critical signaling molecule for controlling synapse density, a key factor that determines cognitive ability. The elevation of brain Mg2+ by oral administration of L-TAMS in intact animals plays a significant role in mediating the therapeutic effects of L-TAMS. The current study sought to elucidate the unique role of threonate. We aimed to understand if threonate acts directly to elevate intraneuronal Mg2+, and why Mg2+ given without threonate is ineffective for enhancing learning and memory ability. We discovered that threonate is naturally present in cerebrospinal fluid (CSF) and oral treatment with L-TAMS elevated CSF threonate. In cultured hippocampal neurons, threonate treatment directly induced an increase in intracellular Mg2+ concentration. Functionally, elevating threonate upregulated expression of NR2B-containing NMDAR, boosted mitochondrial membrane potential (Delta Psi(m)), and increased functional synapse density in neuronal cultures. These effects are unique to threonate, as other common Mg2+ anions failed to have the same results. Mechanistically, threonate's effects were specifically mediated through glucose transporters (GLUTs). We also evaluated the effects of threonate in human neural stem cell-derived neurons, and found it was equally effective at upregulating synapse density. The current study provides an explanation for why threonate is an essential component of L-TAMS and supports the use of L-TAMS to promote cognitive abilities in human. (C) 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.orgilicenses/by/4.0/).

【 授权许可】

Free