TY - JOUR T1 - Altered phosphorylation of the proteasome subunit Rpt6 has minimal impact on synaptic plasticity and learning JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0073-20.2021 SP - ENEURO.0073-20.2021 AU - Samantha L. Scudder AU - Frankie R. Gonzales AU - Kristin K. Howell AU - Ivar S. Stein AU - Lara E. Dozier AU - Stephan G. Anagnostaras AU - Karen Zito AU - Gentry N. Patrick Y1 - 2021/03/03 UR - http://www.eneuro.org/content/early/2021/03/03/ENEURO.0073-20.2021.abstract N2 - Dynamic control of protein degradation via the ubiquitin proteasome system is thought to play a crucial role in neuronal function and synaptic plasticity. The proteasome subunit Rpt6, an AAA ATPase subunit of the 19S regulatory particle, has emerged as an important site for regulation of 26S proteasome function in neurons. Phosphorylation of Rpt6 on serine 120 (S120) can stimulate the catalytic rate of substrate degradation by the 26S proteasome and this site is targeted by the plasticity-related kinase calcium/calmodulin-dependent kinase II (CaMKII), making it an attractive candidate for regulation of proteasome function in neurons. Several in vitro studies have shown that altered Rpt6 S120 phosphorylation can affect the structure and function of synapses. To evaluate the importance of Rpt6 S120 phosphorylation in vivo, we created two mouse models which feature mutations at S120 that block or mimic phosphorylation at this site. We find that peptidase and ATPase activities are upregulated in the phospho-mimetic mutant and downregulated in the phospho-dead mutant (S120 mutated to aspartic acid (S120D) or alanine (S120A), respectively). Surprisingly, these mutations had no effect on basal synaptic transmission, long-term potentiation, and dendritic spine dynamics and density in the hippocampus. Furthermore, these mutants displayed no deficits in cued and contextual fear memory. Thus, in a mouse model that blocks or mimics phosphorylation at this site, either compensatory mechanisms negate these effects, or small variations in proteasome activity are not enough to induce significant changes in synaptic structure, plasticity, or behavior.SIGNIFICANCE:Several studies have shown that phosphorylation of the proteasome subunit Rpt6 at serine-120 (S120) is an important regulatory mechanism for proteasome-dependent control of synapses and plasticity. We generated phospho-dead (S120A) and phospho-mimetic (S120D) knock-in mice to directly evaluate the role of this site. While we observed expected changes in proteasome activity, we surprisingly did not observe significant changes in basal synaptic transmission, hippocampal long-term potentiation, dendritic spine outgrowth, or behavior. This suggests that neurons may utilize additional mechanisms to compensate for alterations in proteasome function in order to mediate the tight control of the synaptic proteome required for proper synaptic structure, function, and plasticity. ER -