Department of Neuroscience, Rosalind Franklin University of Medicine and Science/The Chicago Medical School, North Chicago, Illinois 60064, USA.
J Neurosci. 2010 Sep 8;30(36):12128-37. doi: 10.1523/JNEUROSCI.2474-10.2010.
Deficits in synaptic function, particularly through NMDA receptors (NMDARs), are linked to late-stage cognitive impairments in Alzheimer's disease (AD). At earlier disease stages, however, there is evidence for altered endoplasmic reticulum (ER) calcium signaling in human cases and in neurons from AD mouse models. Despite the fundamental importance of calcium to synaptic function, neither the extent of ER calcium dysregulation in dendrites nor its interaction with synaptic function in AD pathophysiology is known. Identifying the mechanisms underlying early synaptic calcium dysregulation in AD pathogenesis is likely a key component to understanding, and thereby preventing, the synapse loss and downstream cognitive impairments. Using two-photon calcium imaging, flash photolysis of caged glutamate, and patch-clamp electrophysiology in cortical brain slices, we examined interactions between synaptically and ER-evoked calcium release at glutamatergic synapses in young AD transgenic mice. We found increased ryanodine receptor-evoked calcium signals within dendritic spine heads, dendritic processes, and the soma of pyramidal neurons from 3xTg-AD and TAS/TPM AD mice relative to NonTg controls. In addition, synaptically evoked postsynaptic calcium responses were larger in the AD strains, as were calcium signals generated from NMDAR activation. However, calcium responses triggered by back-propagating action potentials were not different. Concurrent activation of ryanodine receptors (RyRs) with either synaptic or NMDAR stimulation generated a supra-additive calcium response in the AD strains, suggesting an aberrant calcium-induced calcium release (CICR) effect within spines and dendrites. We propose that presenilin-linked disruptions in RyR signaling and subsequent CICR via NMDAR-mediated calcium influx alters synaptic function and serves as an early pathogenic factor in AD.
突触功能障碍,尤其是通过 NMDA 受体(NMDAR)的突触功能障碍,与阿尔茨海默病(AD)的晚期认知障碍有关。然而,在疾病的早期阶段,有证据表明人类病例和 AD 小鼠模型的神经元中内质网(ER)钙信号发生改变。尽管钙对突触功能至关重要,但 ER 钙失调在树突中的程度及其在 AD 病理生理学中的突触功能相互作用尚不清楚。确定 AD 发病机制中早期突触钙失调的机制可能是理解并从而预防突触丧失和下游认知障碍的关键组成部分。使用双光子钙成像、光解笼状谷氨酸和皮层脑片的膜片钳电生理学,我们研究了年轻 AD 转基因小鼠中谷氨酸能突触处突触和 ER 诱发钙释放之间的相互作用。我们发现,与非转基因对照相比,3xTg-AD 和 TAS/TPM AD 小鼠的树突棘头、树突突和锥体神经元的体中,ryanodine 受体诱发的钙信号增加。此外,AD 株系中的突触诱发的突触后钙反应更大,NMDAR 激活产生的钙信号也更大。然而,由逆行动作电位触发的钙反应没有差异。ryanodine 受体(RyRs)与突触或 NMDAR 刺激同时激活,在 AD 株系中产生超相加的钙反应,表明棘突和树突内存在异常的钙诱导钙释放(CICR)效应。我们提出,与 presenilin 相关的 RyR 信号中断以及随后通过 NMDAR 介导的钙内流产生的 CICR 改变了突触功能,并作为 AD 的早期致病因素。