Chronic D-serine reverses arc expression and partially rescues dendritic abnormalities in a mouse model of NMDA receptor hypofunction.
Chronic D-serine reverses arc expression and partially rescues dendritic abnormalities in a mouse model of NMDA receptor hypofunction.
复制标题
DOI：
10.1016/j.neuint.2014.05.015
复制
发表时间：
2014-09
影响因子：
4.2
通讯作者：
Coyle JT
中科院分区：
文献类型：
--
作者：
Balu DT;Coyle JT
活性调节的细胞凋亡相关蛋白（Arc）是一种几乎只在多巴胺能神经元中表达的立即早期基因。Arc蛋白在突触后致密物（PSD）中富集，并与N-甲基-D-天冬氨酸受体（NMDAR）复合物共定位。Arc转录受NMDAR活性正调控，对树突棘可塑性很重要。丝氨酸消旋酶（SR-/-）的基因消融（将L-丝氨酸转化为D-丝氨酸的酶，NMDAR的促凝剂）可降低海马中的树突棘密度。在这里，我们证明了SR缺陷（SR-/-）小鼠在海马中也具有减少的Arc蛋白表达，这可以通过成年期慢性D-丝氨酸给药来逆转。此外，D-丝氨酸治疗部分挽救了SR−/−小鼠的海马棘缺陷。这些结果证明了D-丝氨酸在体内调节海马Arc表达的重要性。此外，我们的研究结果强调了使用甘氨酸调节位点激动剂D-丝氨酸治疗由于NMDAR功能减退而表现出Arc和树突棘失调的疾病的潜在效用，例如精神分裂症。
Activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that is expressed almost exclusively in glutamatergic neurons. Arc protein is enriched in the postsynaptic density (PSD) and colocalizes with the N-methyl-D-aspartate receptor (NMDAR) complex. Arc transcription is positively modulated by NMDAR activity and is important for dendritic spine plasticity. Genetic ablation of serine racemase (SR−/−), the enzyme that converts L-serine to D-serine, a coagonist at the NMDAR, reduces dendritic spine density in the hippocampus. Here we demonstrate that SR deficient (SR−/−) mice also have reduced Arc protein expression in the hippocampus that can be reversed with chronic D-serine administration in adulthood. Furthermore, D-serine treatment partially rescues the hippocampal spine deficit in SR−/− mice. These results demonstrate the importance of D-serine in regulating the hippocampal expression of Arc in vivo. In addition, our findings underscore the potential utility of using the glycine modulatory site agonist D-serine to treat disorders that exhibit Arc and dendritic spine dysregulation as a consequence of NMDAR hypofunction, such as schizophrenia.
登录
查看更多内容
DOI：
10.1111/j.1601-183x.2010.00656.x
发表时间：
2011-03
期刊：
Genes, brain, and behavior
影响因子：
--
作者：
DeVito LM;Balu DT;Kanter BR;Lykken C;Basu AC;Coyle JT;Eichenbaum H
通讯作者：
Eichenbaum H
影响因子：
15.9
作者：
Korb E;Finkbeiner S
通讯作者：
Finkbeiner S
影响因子：
16.2
作者：
Steward, O;Worley, PF
通讯作者：
Worley, PF
影响因子：
11
作者：
Basu, A. C.;Tsai, G. E.;Coyle, J. T.
通讯作者：
Coyle, J. T.
影响因子：
11
作者：
Kirov, G.;Pocklington, A. J.;Holmans, P.;Ivanov, D.;Ikeda, M.;Ruderfer, D.;Moran, J.;Chambert, K.;Toncheva, D.;Georgieva, L.;Grozeva, D.;Fjodorova, M.;Wollerton, R.;Rees, E.;Nikolov, I.;van de Lagemaat, L. N.;Bayes, A.;Fernandez, E.;Olason, P. I.;Boettcher, Y.;Komiyama, N. H.;Collins, M. O.;Choudhary, J.;Stefansson, K.;Stefansson, H.;Grant, S. G. N.;Purcell, S.;Sklar, P.;O'Donovan, M. C.;Owen, M. J.
通讯作者：
Owen, M. J.