Translational repressors, increasing evidence suggests, participate in the regulation of protein synthesis at the synapse, thus providing a basis for the long-term plastic modulation of synaptic strength. Dendritic BC1 RNA is a non-protein-coding RNA that represses translation at the level of initiation. However, the molecular mechanism of BC1 repression has remained unknown. Here we identify the catalytic activity of eukaryotic initiation factor 4A (eIF4A), an ATP-dependent RNA helicase, as a target of BC1-mediated translational control. BC1 RNA specifically blocks the RNA duplex unwinding activity of eIF4A but, at the same time, stimulates its ATPase activity. BC200 RNA, the primate-specific BC1 counterpart, targets eIF4A activity in identical fashion, as a result decoupling ATP hydrolysis from RNA duplex unwinding. In vivo, BC1 RNA represses translation of a reporter mRNA with 5 secondary structure. The eIF4A mechanism places BC RNAs in a central position to modulate protein synthesis in neurons.Local protein synthesis at the synapse, increasing evidence suggests, is one of the key molecular mechanisms that underlie input-specific modulations of synaptic strength and consequently higher brain functions that rely on such synaptic plasticity. Translational control mechanisms in synapto-dendritic domains are thought to be essential for the long-term spatiotemporal modulation of mosaic local protein repertoires. Such mechanisms are therefore attracting increasing interest among neuroscientists and molecular and cellular biologists (reviewed in references 3, 11, 24, 26, 27, 51, 60, and 67).At the same time, there has been growing awareness of the biological significance of small, functional RNAs in eukaryotic cells in general and in neurons in particular (2, 7, 11). Small, non-protein-coding RNAs (npcRNAs) (also known as untranslated RNAs) (9) may be particularly well suited as posttranscriptional regulators of gene expression that enhance brainenvironment interactions (11). Neuronal BC1 RNA is a small dendritic npcRNA (64) that operates as a translational repressor (30,65,66). BC1 RNA, which is targeted to dendrites (38,39) and is abundant at the synapse (13), represses translation at the level of initiation (65, 66).In eukaryotes, translation initiation proceeds in three stages, each of which is mediated by a number of eukaryotic initiation factors (eIFs) (reviewed in references 25 and 43). An eukaryotic initiation factor 2 (eIF2) ⅐ GTP ⅐ GMet-tRNA i ternary complex first binds to the 40S ribosomal subunit to form a 43S preinitiation complex. This complex is subsequently recruited to the mRNA, typically to the 5Ј cap structure, and scans to the initiator codon to form a 48S initiation complex. In the final step, this complex is joined by the large ribosomal subunit to form an 80S monoribosome complex ready for elongation. It is frequently the second step, recruitment of the 43S complex and 48S complex assembly, that is rate limiting and the target for regulation. This step is mediated by the eIF4 family of facto...

Translational control at the synapse is thought to be a key determinant of neuronal plasticity. How is such control implemented? We report that small untranslated BC1 RNA is a specific effector of translational control both in vitro and in vivo. BC1 RNA, expressed in neurons and germ cells, inhibits a rate-limiting step in the assembly of translation initiation complexes. A translational repression element is contained within the unique 3′ domain of BC1 RNA. Interactions of this domain with eukaryotic initiation factor 4A and poly(A) binding protein mediate repression, indicating that the 3′ BC1 domain targets a functional interaction between these factors. In contrast, interactions of BC1 RNA with the fragile X mental retardation protein could not be documented. Thus, BC1 RNA modulates translation-dependent processes in neurons and germs cells by directly interacting with translation initiation factors.

BackgroundSingle‐episode anesthetic exposure is the most prevalent surgery‐related incidence among young children in the United States. Although numerous studies have used animals to model the effects of neonatal anesthetics on behavioral changes later on in life, our understanding of the functional consequences to the developing brain in a comprehensive and clinically relevant manner is unclear.MethodsThe volatile anesthetic, sevoflurane (sevo) was administered to C57BL6 postnatal day 7 (P7) mice in a 40% oxygen and 60% nitrogen gas mixture. In order to examine the effects of sevo alone on the developing brain in a clinically relevant manner, mice were exposed to an average of 2.38 ± 0.11% sevo for 2 h. No sevo (control) mice were treated in an identical manner without sevo exposure. Mice were examined for cognition and neuropsychiatric‐like behavioral changes at 1–5 months of age.ResultsUsing the active place avoidance (APA) test and the novel object recognition (NOR) test, we demonstrated that P7 sevo‐treated mice showed a deficit in learning and memory both during periadolescence and adulthood. We then employed a battery of neuropsychiatric‐like behavioral tests to examine social interaction, communication, and repetitive behavior. Interestingly, compared to the no‐sevo–treated group, sevo‐treated mice showed significant reductions in the time interacting with a novel mouse (push–crawl and following), time and interaction in a chamber with a novel mouse, and time sniffing a novel social odor.ConclusionsOur study established that single‐episode, 2‐h sevo treatment during early life impairs cognition later on in life. With this approach, we also observed neuropsychiatric‐like behavior changes such as social interaction deficits in the sevo‐treated mice. This study elucidated the effects of a clinically relevant single‐episode sevo application, given during the neonatal period, on neurodevelopmental behavioral changes later on in life.

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