Huang Ted, McDonough Conor B, Abel Ted
Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Eur J Cell Biol. 2006 Jul;85(7):635-42. doi: 10.1016/j.ejcb.2006.02.005. Epub 2006 Apr 4.
Synaptic plasticity, the activity-dependent change in the strength of neuronal connections, is a proposed cellular mechanism of memory storage that is critically regulated by protein kinases such as cAMP-dependent protein kinase (PKA). Despite the fact that a neuron contains thousands of synapses, the expression of synaptic plasticity can be specific to subsets of synapses. This is surprising because signal transduction pathways underlying synaptic plasticity involve diffusible second messenger molecules such as cAMP and diffusible proteins such as the catalytic subunit of PKA. One way in which this specificity can be achieved is by the localization of signal transduction molecules to specific subcellular domains. Spatial compartmentalization of PKA signaling is achieved via binding to A kinase-anchoring proteins (AKAPs). We report here that pharmacological inhibition of PKA anchoring impairs synaptically activated late-phase long-term potentiation (L-LTP) in hippocampal slices. In contrast, potentiation that is induced by the pharmacological activation of the cAMP/PKA pathway, which can potentially affect all synapses within the neuron, is not impaired by inhibition of PKA anchoring. These results suggest that PKA anchoring may be particularly important for events that occur at the synapse during the induction of L-LTP, such as synaptic tagging and capture. Indeed, our results demonstrate that blocking PKA anchoring impairs synaptic tagging and capture. Thus our data highlight the idea that PKA anchoring may allow for specific populations of synapses to change in synaptic strength in the face of plasticity-related transcription that is cell-wide.
突触可塑性是指神经元连接强度随活动而发生的变化，是一种被提出的记忆存储细胞机制，受到诸如环磷酸腺苷依赖性蛋白激酶（PKA）等蛋白激酶的严格调控。尽管一个神经元包含数千个突触，但突触可塑性的表达可能仅限于突触的特定子集。这很令人惊讶，因为突触可塑性背后的信号转导途径涉及可扩散的第二信使分子，如环磷酸腺苷，以及可扩散的蛋白质，如PKA的催化亚基。实现这种特异性的一种方式是将信号转导分子定位到特定的亚细胞结构域。PKA信号的空间分隔是通过与A激酶锚定蛋白（AKAPs）结合来实现的。我们在此报告，PKA锚定的药理学抑制会损害海马切片中突触激活的晚期长时程增强（L-LTP）。相比之下，由环磷酸腺苷/PKA途径的药理学激活诱导的增强，这种增强可能会潜在地影响神经元内的所有突触，并不会因PKA锚定的抑制而受损。这些结果表明，PKA锚定对于L-LTP诱导过程中突触发生的事件，如突触标记和捕获，可能特别重要。事实上，我们的结果表明，阻断PKA锚定会损害突触标记和捕获。因此，我们的数据突出了这样一种观点，即PKA锚定可能允许特定的突触群体在面对全细胞范围的可塑性相关转录时改变突触强度。
