Balu Darrick T, Coyle Joseph T
Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA; Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, Belmont, MA 02478, USA.
Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA; Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, Belmont, MA 02478, USA.
Neurochem Int. 2014 Sep;75:76-8. doi: 10.1016/j.neuint.2014.05.015. Epub 2014 Jun 7.
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.
活性调节细胞骨架相关蛋白（Arc）是一种即刻早期基因，几乎仅在谷氨酸能神经元中表达。Arc蛋白在突触后致密区（PSD）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活性正向调节，对树突棘可塑性很重要。丝氨酸消旋酶基因敲除（SR-/-）小鼠中，将L-丝氨酸转化为D-丝氨酸（NMDAR的一种协同激动剂）的酶缺失，海马体中的树突棘密度降低。在此我们证明，SR缺陷（SR-/-）小鼠海马体中的Arc蛋白表达也降低，成年期长期给予D-丝氨酸可使其逆转。此外，D-丝氨酸治疗可部分挽救SR-/-小鼠的海马体棘突缺陷。这些结果证明了D-丝氨酸在体内调节海马体Arc表达中的重要性。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-丝氨酸治疗因NMDAR功能减退而表现出Arc和树突棘失调的疾病（如精神分裂症）的潜在效用。
