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• Composition of mRNPs is dynamic across space and time. • mRNPs in dendrites and axons share common features of diffusion and directed transport. • HMM Bayes approach is a useful tool to analyze mRNA transport dynamics. • mRNA localization and local translation in response to synaptic activity are important for long-lasting plasticity. Neurons are highly polarized cells that can extend processes far from the cell body. As such, transport of messenger RNAs serves as a set of blueprints for the synthesis of specific proteins at distal sites. RNA localization to dendrites and axons confers the ability to regulate translation with extraordinary precision in space and time. Although the rationale for RNA localization is quite compelling, it is unclear how a neuron orchestrates such a complex task of distributing over a thousand different mRNAs to their respective subcellular compartments. Recent single-molecule imaging studies have led to insights into the kinetics of individual mRNAs. We can now peer into the transport dynamics of mRNAs in both dendrites and axons. [ABSTRACT FROM AUTHOR]

Fragile X syndrome (FXS) is a leading cause of inherited intellectual disability and autism. Whereas dysregulated RNA translation in Fmr1 knockout (KO) mice, a model of FXS, is well studied, little is known about aberrant transcription. Using single-molecule mRNA detection, we show that mRNA encoding the AMPAR subunit GluA2 (but not GluA1) is elevated in dendrites and at transcription sites of hippocampal neurons of Fmr1 KO mice, indicating elevated GluA2 transcription. We identify CPEB3, a protein implicated in memory consolidation, as an upstream effector critical to GluA2 mRNA expression in FXS. Increased GluA2 mRNA is translated into an increase in GluA2 subunits, a switch in synaptic AMPAR phenotype from GluA2-lacking, Ca2+-permeable to GluA2-containing, Ca2+-impermeable, reduced inhibitory synaptic transmission, and loss of NMDAR-independent LTP at glutamatergic synapses onto CA1 inhibitory interneurons. These factors could contribute to an excitatory/inhibitory imbalance—a common theme in FXS and other autism spectrum disorders. [Display omitted] • Transcription of GluA2 mRNA is elevated in Fmr1- deficient hippocampal neurons • CPEB3 and STAT5b are the upstream effectors critical to GluA2 mRNA expression • Increase in GluA2 underlies a switch in synaptic AMPAR phenotype in CA1 interneurons • A switch in AMPAR phenotype causes deficits in synaptic transmission and plasticity Using single-molecule FISH and patch-clamp recording, Hwang et al. show that dysregulation of GluA2 transcription is critical to synaptic function in an animal model of autism. The increase in GluA2 results in a switch in AMPAR phenotype and deficits in synaptic transmission and plasticity at synapses onto CA1 inhibitory interneurons. [ABSTRACT FROM AUTHOR]

Targeting of mRNAs to neuronal dendrites and axons plays an integral role in intracellular signaling, development, and synaptic plasticity. Single-molecule imaging of mRNAs in neurons and brain tissue has led to enhanced understanding of mRNA dynamics. Here we discuss aspects of mRNA regulation as revealed by single-molecule detection, which has led to quantitative analyses of mRNA diversity, localization, transport, and translation. These exciting new discoveries propel our understanding of the life of an mRNA in a neuron and how its activity is regulated at the single-molecule level. [ABSTRACT FROM AUTHOR]