FIGURE 1.

Differential local roles of the proteasome in dendrites and in the nucleus during L-LTP. (A) Proteasome Active: the proteasome in dendrites is highly active, translational activators such as eIF4E are degraded (broken green spheres) and protein substrates that positively regulate L-LTP are degraded (broken spheres). Therefore extent of L-LTP is limited and only normal L-LTP ensues. A retrograde signal is likely transmitted to the nucleus. Proteasome aids transcription of genes by degrading the CREB repressor ATF4 (broken squares in the nucleus) thus allowing for normal L-LTP maintenance. Transcribed mRNAs (triangles) travel to activated synapses. (B) Proteasome Inactive: when the proteasome is inhibited (indicated by X marks on the proteasome), translational activators are stabilized (intact green spheres) leading to increased protein synthesis in dendrites. Also the newly synthesized proteins in dendrites are stabilized (intact spheres) and L-LTP-inducing stimulation protocols dramatically increase (upward arrow) the early part of L-LTP (Ep-L-LTP). Proteasome inhibition obstructs CREB-mediated transcription by preventing the degradation of transcription repressor ATF4 (intact squares in the nucleus). Proteasome inhibition could also inhibit the generation of the retrograde signal. Therefore, L-LTP is not maintained but decays (downward arrow). Proteasome inhibition also causes failure of sustained translation because of stabilization of translation repressors such as 4E-BP (intact red spheres) which accumulate after induction of L-LTP thus contributing to blockade of L-LTP maintenance. [Modified from Hegde (2010) and reprinted with permission from Cold Spring Harbor Laboratory Press].