Author(s): Zheng Z, Keifer J
The cyclic AMP-dependent protein kinase (PKA) signaling pathway has been shown to be important in mechanisms of synaptic plasticity, although its direct and downstream signaling effects are not well understood. Using an in vitro model of eyeblink classical conditioning, we report that PKA has a critical role in initiating a signaling cascade that results in synaptic delivery of glutamate receptor 1 (GluR1)- and GluR4-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in abducens motor neurons during conditioning. PKA and the Ca(2+)-calmodulin-dependent protein kinases (CaMKs) II and IV are activated early in conditioning and are required for acquisition and expression of conditioned responses (CRs). cAMP-response-element-binding protein (CREB) is also activated early in conditioning but is blocked by coapplication of inhibitors to PKA and the CaMKs, suggesting that CREB is downstream of those signaling cascades. Moreover, evidence suggests that PKA activates extracellular signal-regulated kinase, which is also required for conditioning. Imaging studies after conditioning further indicate that colocalization of GluR1 AMPAR subunits with the synaptic marker synaptophysin requires PKA, but is insensitive to the N-methyl-d-aspartate receptor (NMDAR) inhibitor d,l-AP5. PKA activation also leads to synaptic localization of GluR4 subunits that, unlike GluR1, is dependent on NMDARs and is mediated by CaMKII. Together with previous studies, our findings support a two-stage model of AMPAR synaptic delivery during acquisition of classical conditioning. The first stage involves synaptic incorporation of GluR1-containing AMPARs that serves to activate silent synapses. This allows a second stage of NMDAR- and protein kinase C-dependent delivery of GluR4 AMPAR subunits that supports the acquisition of CRs.
Referred From: https://www.ncbi.nlm.nih.gov/pubmed/19261706
Author(s): Isaac JT, Nicoll RA, Malenka RC
Author(s): Liao D, Hessler NA, Malinow R
Author(s): Durand GM, Kovalchuk Y, Konnerth A
Author(s): Liao D, Scannevin RH, Huganir R
Author(s): Dias RB, Ribeiro JA, Sebastião AM
Author(s): Esteban JA, Shi SH, Wilson C, Nuriya M, Huganir RL, et al.
Author(s): Lu W, Man H, Ju W, Trimble WS, MacDonald JF, et al.
Author(s): Kolleker A, Zhu JJ, Schupp BJ, Qin Y, Mack V, et al.
Author(s): Man HY, Sekine-Aizawa Y, Huganir RL
Author(s): Ehlers MD
Author(s): Cousin MA, Evans GJ
Author(s): Ouardouz M, Xu JY, Sastry BR
Author(s): Banke TG, Bowie D, Lee H, Huganir RL, Schousboe A, et al.
Author(s): Rothermel JD, Stec WJ, Baraniak J, Jastorff B, Botelho LH
Author(s): Pieroni JP, Jacobowitz O, Chen J, Iyengar R
Author(s): Rens-Domiano S, Hamm HE
Author(s): Oldham WM, Hamm HE
Author(s): Bredt DS, Nicoll RA
Author(s): Barry MF, Ziff EB
Author(s): Santos SD, Carvalho AL, Caldeira MV, Duarte CB