Old Enough to Remember?

Abstract

Long-term potentiation (LTP) is a form of synaptic plasticity thought to mediate learning and memory in hippocampal neurons. At a molecular level, neuronal function is altered during LTP when AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) neurotransmitter receptors accumulate in postsynaptic sites. This movement of receptors is promoted by PKA (cyclic AMP-dependent protein kinase). Lu et al. explored the role of a scaffolding protein, AKAP150, that positions PKA appropriately so that it can phosphorylate AMPA receptors. When the authors examined mice expressing a mutant form of AKAP150 that doesn’t bind PKA, they found that its effects were strongly dependent on the age of the mice examined. LTP induced by a single tetanic electrical stimulus was normal in animals 4 weeks old but was not detected in animals 7 to 12 weeks old. Inhibitors of PKA or of AMPA receptors that lack the GluR2 subunit also blocked LTP in 8-week-old mice but not in 4-week-old mice. (AMPA receptors that lack GluR2 contain the GluR1 subunit that is a substrate for PKA.) Thus, the authors propose that mice undergo two developmental transitions: They require PKA for LTP for the first few weeks of life, don’t need it around 4 weeks of age, and then again need PKA’s actions for LTP at around 8 weeks of age. This might reflect changes in function of the developing brain. In the immature brain, neurons may not be ready to form permanent synaptic connections, so LTP may be restrained by additional requirements--activation of PKA and GluR2-lacking AMPA receptors. The older brain may have a period of increased LTP (during which requirements are relaxed, i.e., PKA is not required) and then undergo restriction as the brain becomes more mature and connections are stabilized. (The authors carefully note other studies that provide contrasting results regarding the precise ages at which PKA signaling is required and whether GluR2-lacking receptors are the main ones used in 8-week-old animals.) Y. Lu, M. Allen, A. R. Halt, M. Weisenhaus, R. F. Dallapiazza, D. D. Hall, Y. M. Usachev, G. S. McKnight, J. W. Hell, Age-dependent requirement of AKAP150-anchored PKA and GluR2-lacking AMPA receptors in LTP. EMBO J. 26 , 4879-4890 (2007). [PubMed]