SummaryNeuronal activity regulates the transcription and translation of the immediate-early gene Arc/Arg3.1, a key mediator of synaptic plasticity. Proteasome-dependent degradation of Arc tightly limits its temporal expression, yet the significance of this regulation remains unknown. We disrupted the temporal control of Arc degradation by creating an Arc knockin mouse (ArcKR) where the predominant Arc ubiquitination sites were mutated. ArcKR mice had intact spatial learning but showed specific deficits in selecting an optimal strategy during reversal learning. This cognitive inflexibility was coupled to changes in Arc mRNA and protein expression resulting in a reduced threshold to induce mGluR-LTD and enhanced mGluR-LTD amplitude. These findings show that the abnormal persistence of Arc protein limits the dynamic range of Arc signaling pathways specifically during reversal learning. Our work illuminates how the precise temporal control of activity-dependent molecules, such as Arc, regulates synaptic plasticity and is crucial for cognition.

Synaptic plasticity relies on rapid, yet spatially precise signaling to alter synaptic strength. Arc is a brain enriched protein that is rapidly expressed during learning-related behaviors and is essential for regulating metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD). We previously showed that disrupting the ubiquitination capacity of Arc enhances mGluR-LTD; however, the consequences of Arc ubiquitination on other mGluR-mediated signaling events is poorly characterized. Here we find that pharmacological activation of Group I mGluRs with S-3,5-dihydroxyphenylglycine (DHPG) increases Ca2+ release from the endoplasmic reticulum (ER). Disrupting Arc ubiquitination on key amino acid residues enhances DHPG-induced ER-mediated Ca2+ release. These alterations were observed in all neuronal subregions except secondary branchpoints. Deficits in Arc ubiquitination altered Arc self-assembly and enhanced its interaction with calcium/calmodulin-dependent protein kinase IIb (CaMKIIb) and constitutively active forms of CaMKII in HEK293 cells. Colocalization of Arc and CaMKII was altered in cultured hippocampal neurons, with the notable exception of secondary branchpoints. Finally, disruptions in Arc ubiquitination were found to increase Arc interaction with the integral ER protein Calnexin. These results suggest a previously unknown role for Arc ubiquitination in the fine tuning of ER-mediated Ca2+ signaling that may support mGluR-LTD, which in turn, may regulate CaMKII and its interactions with Arc.

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The Imaging X-ray Polarimetry Explorer (IXPE) will expand the information space for study of cosmic sources, by adding linear polarization to the properties (time, energy, and position) observed in x-ray astronomy. Selected in 2017 January as a NASA Astrophysics Small Explorer (SMEX) mission, IXPE will be launched into an equatorial orbit in 2021. The IXPE mission will provide scientifically meaningful measurements of the x-ray polarization of a few dozen sources in the 2-8 keV band, including polarization maps of several x-ray-bright extended sources and phase-resolved polarimetry of many bright pulsating x-ray sources.

Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates of the microtubule-associated protein tau, a main component of neurofibrillary tangles. Alzheimers disease (AD) is the most common type of secondary tauopathy. While stabilizing microtubules is a well-established role for tau, tau is also localized at postsynaptic sites and can disrupt synaptic plasticity when knocked out or overexpressed. A major gap in understanding tau functions is identifying the intracellular mechanisms through which tau modulates synaptic function. Here, we found that overexpression of the 0N4R isoform of tau in HEK 293 cells decreased the stability of the activity-regulated cytoskeleton-associated protein (Arc), an immediate early gene that plays a key role in synaptic plasticity, learning and memory. Importantly, tau-induced Arc degradation was found to be isoform-specific in that overexpression of the 0N3R tau isoform had no effect. Tau-dependent reduction of Arc required proteasome activity, yet was independent of Arc ubiquitination. Surprisingly, tau-induced Arc removal required the endophilin-binding domain of Arc. Overexpression of 0N4R tau in primary hippocampal neurons led to Arc instability exclusively in neuronal dendrites, which was coupled to increases in the expression of dendritic and somatic surface GluA1-containing AMPA receptors. Interestingly, these effects on Arc stability and GluA1 localization were not observed in the commonly studied tau mutant, P301L. Our findings implicate isoform- and domain-specific effects of tau in regulating Arc stability and AMPA receptor targeting, which may in part explain the deficits in synaptic plasticity that are observed in select types of tauopathies.