Local protein synthesis has a significant role in long-term memory storage (LTM) in the marine snailAplysia,6-10the fruit flyDrosophila,11,12and in mice.13-16Localization of specific mRNAs provides an efficient regulatory mechanism for restricting gene expression to specific subcellular locations in neurons and an elegant mechanism for synapse-specific plasticity.9,17It allows individual synapses to undergo specific changes such as remodeling and growth in response to specific stimuli, such as learning. translation, memory PC786 storage, signaling network, synapses Groundbreaking observations by Steward and Levy on polysome localization at the base of dendritic spines challenged the view that proteins present at the synapse are synthesized in the cell body and transported to the synapses.1Their observations suggested that mRNAs and the machinery for protein translation are transported to synapses. Several later studies have shown that RNAs are localized to distal parts of neurons in both vertebrates and invertebrates. Sequencing of RNAs prepared from microdissected neuronal processes of sensory neurons ofAplysialed to the identification of a few hundred RNAs that are enriched in neuronal processes.2,3Using a microarray-based approach, RNAs localized to dendrites of hippocampal neurons were recognized.4Recently, RNaseq analysis identified a few thousand RNAs localized to the dendritic layer of the hippocampus.5 == What Is the Significance of Transcriptome Localized to Synapses? == Several studies have shown that RNAs localized to synapses are used for synthesizing new proteins, which are necessary for synaptogenesis and activity-dependent synaptic remodeling. Local protein synthesis has a significant role in long-term memory storage (LTM) in the marine snailAplysia,6-10the fruit flyDrosophila,11,12and in mice.13-16Localization of specific mRNAs provides an efficient regulatory mechanism for restricting gene expression to specific subcellular locations in neurons and an elegant mechanism for synapse-specific plasticity.9,17It allows individual synapses to undergo specific changes such as remodeling and growth in response to specific stimuli, such as learning. Such modifications can occur independently of unstimulated synapses in a prolonged, protein synthesis-dependent manner. In a study using bifurcated sensory neurons of PC786 the marine snailAplysia, Martin and colleagues described the role of mRNA translation during synapse-specific long-term facilitation (LTF).9Synapse-specific translation is also critical for long-term potentiation (LTP) in the hippocampus.18LTF and LTP are considered the cellular analogs of learning and memory storage. These studies utilized pharmacological inhibition of translation and electrophysiological measurements of the consequences of protein synthesis inhibition. Recently, synaptic translation of specific mRNAs has been visualized in the sensory neurons ofAplysia19and inDrosophila20,21by state-of-the-art imaging methodologies. == What Determines Localization and Composition of Transcriptome at the Synapse? == You will find two main factors that determine localization of specific RNAs and composition of synaptic transcriptome: transcriptional activation of specific genes in the nucleus, and active transport of mRNAs from cell body to synapses. Studies that have used models such asAplysia,Drosophila, and mice suggest that activation of several genes occurs during learning and memory processes. In the isolatedAplysiasensory to motor neuron cultures and in the intact animal, repeated exposure to serotonin (5-HT) causes a larger increase in cAMP, leading to the activation and translocation of PKA and MAP kinase to the nucleus. This translocation activates CREB1-dependent transcription and represses CREB2, leading to the induction of several immediate early genes.8,22-25A comparable sequence of second messenger signaling and gene induction was also found to have been recruited for long-term memory storage inDrosophilaand in mice.26-31 Two specific genes of interest that are activated inAplysiasensory neurons in response to 5-HT exposure are specific isoforms of molecular motor kinesin heavy chain (ApKHC1), and kinesin light chain (ApKLC2). Kinesin was first recognized by Brady32and Vale et al.,33and is composed of two heavy chains (KHC) and two light chains (KLC). PC786 The super families of kinesin proteins (KIFs) are the molecular motors that transport cargos along microtubules. More than 40 KIFs have been recognized in mammals.34,35Kinesins were found to mediate the transport of RNAs and proteins from cell body to synapses.34To understand the functions of the KIFs, several biochemical and genetic attempts were made to identify molecules carried by KIFs. This has led to the identification of several cargo proteins. For example, KIF17 binds to mLin-10 to transport the NMDA receptor in dendrites.36,37Using the tail region of KIF5 as bait in affinity chromatography, Kanai et al. recognized 42 proteins, including several known RNA-binding proteins that interact with kinesin, as well as few transported Rabbit Polyclonal to CHRNB1 mRNAs (CAMKII and Arc).38 == Is the Kinesin-Mediated Transport of Proteins and RNAs Important for LTM? == In response to 5-HT, a modulatory transmitter released during behavioral sensitization, a specific isoform of the kinesin-heavy chain ApKHC1, is usually transcriptionally upregulated in PC786 both pre- and post-synaptic neurons of theAplysiagill withdrawal reflex. We find that ApKHC1 knockdown in either the pre- or post-synaptic neurons blocked the establishment of LTF. However, it did not impact short-term facilitation (STF) or persistence of LTF, suggesting that during the early phase of memory storage, kinesin transports crucial molecules that are later utilized for persistence of memory (Fig. 1). Indeed, several synaptic proteins required.
