FXR1P Limits Long-Term Memory, Long-Lasting Synaptic Potentiation, and De Novo GluA2 Translation

SummaryTranslational control of mRNAs allows for rapid and selective changes in synaptic protein expression that are required for long-lasting plasticity and memory formation in the brain. Fragile X Related Protein 1 (FXR1P) is an RNA-binding protein that controls mRNA translation in nonneuronal cells and colocalizes with translational machinery in neurons. However, its neuronal mRNA targets and role in the brain are unknown. Here, we demonstrate that removal of FXR1P from the forebrain of postnatal mice selectively enhances long-term storage of spatial memories, hippocampal late-phase long-term potentiation (L-LTP), and de novo GluA2 synthesis. Furthermore, FXR1P binds specifically to the 5′ UTR of GluA2 mRNA to repress translation and limit the amount of GluA2 that is incorporated at potentiated synapses. This study uncovers a mechanism for regulating long-lasting synaptic plasticity and spatial memory formation and reveals an unexpected divergent role of FXR1P among Fragile X proteins in brain plasticity

Na+-affinity and relation to transport kinetics of Na+/Ca2+-K+ exchanger NCKX2

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Divergent Synaptic Scaling of Miniature EPSCs following Activity Blockade in Dissociated Neuronal Cultures

Neurons can respond to decreased network activity with a homeostatic increase in the amplitudes of miniature EPSCs (mEPSCs). The prevailing view is that mEPSC amplitudes are uniformly multiplied by a single factor, termed “synaptic scaling.” Deviations from purely multiplicative scaling have been attributed to biological differences, or to a distortion imposed by a detection threshold limit. Here, we demonstrate in neurons dissociated from cortices of male and female mice that the shift in mEPSC amplitudes observed in the experimental data cannot be reproduced by simulation of uniform multiplicative scaling, with or without the distortion caused by applying a detection threshold. Furthermore, we demonstrate explicitly that the scaling factor is not uniform but is close to 1 for small mEPSCs, and increases with increasing mEPSC amplitude across a substantial portion of the data. This pattern was also observed for previously published data from dissociated mouse hippocampal neurons and dissociated rat cortical neurons. The finding of “divergent scaling” shifts the current view of homeostatic plasticity as a process that alters all synapses on a neuron equally to one that must accommodate the differential effect observed for small versus large mEPSCs. Divergent scaling still accomplishes the essential homeostatic task of modifying synaptic strengths in the opposite direction of the activity change, but the consequences are greatest for those synapses which individually are more likely to bring a neuron to threshold. SIGNIFICANCE STATEMENT In homeostatic plasticity, the responses to chronic increases or decreases in network activity act in the opposite direction to restore normal activity levels. Homeostatic plasticity is likely to play a role in diseases associated with long-term changes in brain function, such as epilepsy and neuropsychiatric illnesses. One homeostatic response is the increase in synaptic strength following a chronic block of activity. Research is focused on finding a globally expressed signaling pathway, because it has been proposed that the plasticity is uniformly expressed across all synapses. Here, we show that the plasticity is not uniform. Our work suggests that homeostatic signaling molecules are likely to be differentially expressed across synapses

Divergent Synaptic Scaling of Miniature EPSCs following Activity Blockade in Dissociated Neuronal Cultures

Neurons can respond to decreased network activity with a homeostatic increase in the amplitudes of miniature EPSCs (mEPSCs). The prevailing view is that mEPSC amplitudes are uniformly multiplied by a single factor, termed “synaptic scaling.” Deviations from purely multiplicative scaling have been attributed to biological differences, or to a distortion imposed by a detection threshold limit. Here, we demonstrate in neurons dissociated from cortices of male and female mice that the shift in mEPSC amplitudes observed in the experimental data cannot be reproduced by simulation of uniform multiplicative scaling, with or without the distortion caused by applying a detection threshold. Furthermore, we demonstrate explicitly that the scaling factor is not uniform but is close to 1 for small mEPSCs, and increases with increasing mEPSC amplitude across a substantial portion of the data. This pattern was also observed for previously published data from dissociated mouse hippocampal neurons and dissociated rat cortical neurons. The finding of “divergent scaling” shifts the current view of homeostatic plasticity as a process that alters all synapses on a neuron equally to one that must accommodate the differential effect observed for small versus large mEPSCs. Divergent scaling still accomplishes the essential homeostatic task of modifying synaptic strengths in the opposite direction of the activity change, but the consequences are greatest for those synapses which individually are more likely to bring a neuron to threshold. SIGNIFICANCE STATEMENT In homeostatic plasticity, the responses to chronic increases or decreases in network activity act in the opposite direction to restore normal activity levels. Homeostatic plasticity is likely to play a role in diseases associated with long-term changes in brain function, such as epilepsy and neuropsychiatric illnesses. One homeostatic response is the increase in synaptic strength following a chronic block of activity. Research is focused on finding a globally expressed signaling pathway, because it has been proposed that the plasticity is uniformly expressed across all synapses. Here, we show that the plasticity is not uniform. Our work suggests that homeostatic signaling molecules are likely to be differentially expressed across synapses