Department of Biology, College of Chemical and Life Sciences, University of Maryland, College Park, MD, USA.
J Neurophysiol. 2010 Jan;103(1):479-89. doi: 10.1152/jn.00835.2009. Epub 2009 Nov 11.
Activity-dependent changes in excitatory synaptic transmission in the CNS have been shown to depend on the regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). In particular, several lines of evidence suggest that reversible phosphorylation of AMPAR subunit glutamate receptor 1 (GluR1, also referred to as GluA1 or GluR-A) plays a role in long-term potentiation (LTP) and long-term depression (LTD). We previously reported that regulation of serines (S) 831 and 845 on the GluR1 subunit may play a critical role in bidirectional synaptic plasticity in the Schaffer collateral inputs to CA1. Specifically, gene knockin mice lacking both S831 and S845 phosphorylation sites ("double phosphomutants"), where both serine residues were replaced by alanines (A), showed a faster decaying LTP and a deficit in LTD. To determine which of the two phosphorylation sites was responsible for the phenotype, we have now generated two lines of gene knockin mice: one that specifically lacks S831 (S831A mutants) and another that lacks only S845 (S845A mutants). We found that S831A mutants display normal LTP and LTD, whereas S845A mutants show a specific deficit in LTD. Taken together with our previous results from the "double phosphomutants," our data suggest that either S831 or S845 alone may support LTP, whereas the S845 site is critical for LTD expression.
中枢神经系统中兴奋性突触传递的活性依赖性变化已被证明依赖于α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的调节。特别是，有几条证据表明，AMPAR 亚基谷氨酸受体 1（GluR1，也称为 GluA1 或 GluR-A）的可逆磷酸化在长时程增强（LTP）和长时程抑制（LTD）中起作用。我们之前报道过，GluR1 亚基上丝氨酸（S）831 和 845 的调节可能在 Schaffer 侧支输入到 CA1 的双向突触可塑性中起关键作用。具体而言，缺乏 S831 和 S845 磷酸化位点（“双磷酸突变体”）的基因敲入小鼠，其中两个丝氨酸残基被丙氨酸（A）取代，表现出更快衰减的 LTP 和 LTD 缺陷。为了确定两个磷酸化位点中的哪一个负责表型，我们现在已经生成了两条基因敲入小鼠系：一条特异性缺乏 S831（S831A 突变体），另一条仅缺乏 S845（S845A 突变体）。我们发现 S831A 突变体显示正常的 LTP 和 LTD，而 S845A 突变体显示 LTD 特异性缺陷。与我们之前来自“双磷酸突变体”的结果结合起来，我们的数据表明，S831 或 S845 中的任一个都可能支持 LTP，而 S845 位点对于 LTD 表达至关重要。
