Long-lasting forms of synaptic plasticity and memory are dependent on new protein synthesis. Recent advances obtained from genetic, physiological, pharmacological, and biochemical studies provide strong evidence that translational control plays a key role in regulating long-term changes in neural circuits and thus long-term modifications in behavior. Translational control is important for regulating both general protein synthesis and synthesis of specific proteins in response to neuronal activity. In this review, we summarize and discuss recent progress in the field and highlight the prospects for better understanding of long-lasting changes in synaptic strength, learning, and memory and implications for neurological diseases.

The late phase of long-term potentiation (LTP) and memory (LTM) requires new gene expression, but the molecular mechanisms that underlie these processes are not fully understood. Phosphorylation of eIF2alpha inhibits general translation but selectively stimulates translation of ATF4, a repressor of CREB-mediated late-LTP (L-LTP) and LTM. We used a pharmacogenetic bidirectional approach to examine the role of eIF2alpha phosphorylation in synaptic plasticity and behavioral learning. We show that in eIF2alpha(+/S51A) mice, in which eIF2alpha phosphorylation is reduced, the threshold for eliciting L-LTP in hippocampal slices is lowered, and memory is enhanced. In contrast, only early-LTP is evoked by repeated tetanic stimulation and LTM is impaired, when eIF2alpha phosphorylation is increased by injecting into the hippocampus a small molecule, Sal003, which prevents the dephosphorylation of eIF2alpha. These findings highlight the importance of a single phosphorylation site in eIF2alpha as a key regulator of L-LTP and LTM formation.

Studies on various forms of synaptic plasticity have demonstrated a link between mRNA translation, learning and memory. Like memory, synaptic plasticity includes an early phase which depends on modification of pre-existing proteins, and a late phase that requires transcription and synthesis of new proteins 1,2 . Activation of post-synaptic targets appears to trigger the transcription of plasticityrelated genes. The new mRNAs are either translated in the soma or transported to synapses before translation. GCN2, a key protein kinase, regulates the initiation of translation. We now report a unique feature of hippocampal slices from GCN2 -/-mice: in CA1, a single 100 Hz train induces a strong and sustained long-term potentiation (late-LTP or L-LTP), which is transcription and translation dependent. In contrast, stimulation that elicits late-LTP in wild type slices, such as four 100 Hz trains or forskolin, fails to evoke L-LTP in GCN2 -/-slices. This aberrant synaptic plasticity is mirrored in the behavior of GCN2 -/-mice in the Morris water maze: after weak training, their spatial memory is enhanced, but it is impaired after more intense training. Activated GCN2 stimulates mRNA translation of ATF4, a CREB antagonist. Accordingly, in the hippocampus of GCN2 -/-mice, the expression of ATF4 is reduced and CREB activity is increased. Our study provides genetic, physiological, behavioral and molecular evidence that GCN2 regulates synaptic plasticity, as well as learning and memory through modulation of the ATF4/CREB pathway.Translation of eukaryotic mRNAs is primarily regulated at the level of initiation 3 . Binding of the initiator tRNA, Met-tRNA i Met , to the 40S subunit is facilitated by the initiation factor 2 (eIF2) which forms a ternary complex with GTP and Met-tRNA i Met . Although phosphorylation

In brain, mRNAs are transported from the cell body to the processes, allowing for local protein translation at sites distant from the nucleus. Using subcellular fractionation, we isolated a fraction from rat embryonic day 18 brains enriched for structures that resemble amorphous collections of ribosomes. This fraction was enriched for the mRNA encoding beta-actin, an mRNA that is transported in dendrites and axons of developing neurons. Abundant protein components of this fraction, determined by tandem mass spectrometry, include ribosomal proteins, RNA-binding proteins, microtubule-associated proteins (including the motor protein dynein), and several proteins described only as potential open reading frames. The conjunction of RNA-binding proteins, transported mRNA, ribosomal machinery, and transporting motor proteins defines these structures as RNA granules. Expression of a subset of the identified proteins in cultured hippocampal neurons confirmed that proteins identified in the proteomics were present in neurites associated with ribosomes and mRNAs. Moreover many of the expressed proteins co-localized together. Time lapse video microscopy indicated that complexes containing one of these proteins, the DEAD box 3 helicase, migrated in dendrites of hippocampal neurons at the same speed as that reported for RNA granules. Although the speed of the granules was unchanged by activity or the neurotrophin brain-derived neurotrophic factor, brain-derived neurotrophic factor, but not activity, increased the proportion of moving granules. These studies define the isolation and composition of RNA granules expressed in developing brain.