Figure 1. Post-translational processing and trafficking of secreted and transmembrane proteins in neurons (a) During and after translation, secreted and transmembrane proteins receive post-translational modifications (text, left) as they pass through the endoplasmic reticulum (ER), Golgi apparatus, and trans-Golgi network (TGN). Finally, vesicles containing the proteins bud from the TGN and are transported to their final destination. Targeting mechanisms guide the vesicles to the axon or dendrites and then to the correct area within each where they are secreted or inserted into the plasma membrane. In a process called transcytosis (center), some axonal membrane proteins are first inserted into the dendritic plasma membrane and then re-internalized and trafficked to the axon. (b) Transmembrane proteins, including neurotransmitter receptors, can also be removed from and inserted into the membrane at synapses. Stimulation changes the number of receptors at a synapse which determines the magnitude of synaptic transmissions. On the presynaptic side there are clear vesicles that contain conventional neurotransmitters (e.g. Glutamate, GABA) as well as dense-core vesicles that contain neuropeptides. (c) Many neuropeptides are produced by cleavage of a single large precursor called a pre-propeptide in the Golgi and TGN. Illustrated, a precursor called proopiomelanocortin (POMC) is cleaved up to eight times to form up to ten different neuropeptides. (From Castro MG & Morrison E. (1997) Critical Reviews in Neurobiology 11(1): 35–57). (d) As a transmembrane protein is translated, signal sequences in the protein cause it to cross the ER membrane in a certain orientation. Secreted proteins cross the ER membrane a single time. Multiple signal sequences can cause the protein to cross the ER membrane many times (not shown) (Adapted from: Lodish et al. 2004).

Figure 2. In vitro models used to study protein synthesis in neurons (a) Hippocampal slices are slabs of brain tissue cut from an area of the brain called the hippocampus. Stimulation of axons in the slice elicits synaptic transmission. Certain types of stimulation cause long term changes in the magnitude of future synaptic transmission. High frequency stimulation causes a long term increase in the magnitude of future transmission (plotted as % of baseline). Low frequency stimulation causes a long term decrease. Translation inhibitors can be applied to the slice to show that these long term changes require translation. (From Sawtell NB, Philpot BD & Bear MF (2001) Activity-dependent plasticity of glutamatergic synaptic transmission in the cerebral cortex, in J Kass (ed.) The Mutable Brain: Dynamic and Plasitic Features of the Developing and Mature Brain Amsterdam Harwood Academic Publishers pp. 49–91). (b) Neurons from the sea slug Aplysia can be dissected and arranged to form synapses in specific configurations. Here, a sensory neuron makes synapses with two motor neurons. This allows neurotransmitter to be applied to a single synapse which is generally not possible in preparations of vertebrate neurons. The magnitude of synaptic transmission only increases at the synapse where neurotransmitter was applied (right). Translation inhibitors can be applied locally to show persistence of this change requires local translation only at the activated synapse. (Neurons diagram from Martin et al. Cell 91: 927–938. 1997; graphs from Casadio et al. Cell 99: 221–237. 1999.). (c) Cells in the brain can be dissociated and grown as a single cell layer. This is useful for biochemical studies and visualizing the location of proteins and mRNAs in intact neurons. (d) Grinding up the brain and centrifuging the homogenate results in a sub-cellular fraction called synaptoneurosomes that is enriched in synaptic compartments (By courtesy of Anna Klintsova; http://www.itg.uiuc.edu/exhibits/gallery/pages/image-49.htm). This fraction is useful for biochemical studies of synapses, but can be unreliable due to contamination with other cellular fragments.

Figure 3. Signal transduction pathways that lead to translation and transcription in neurons. Extracellular ligands bind cell surface receptors coupled to cascades of molecular interactions that cause translation and transcription. Note that most pathways directly or indirectly target the initiation complex, formation of which is the rate limiting step in translation. The pathways illustrated are greatly simplified. A single type of receptor can activate many pathways and different pathways interact extensively. Each pathway “component” is often a complex of subunits. After a pathway is activated, additional molecules are required to deactivate it as well as the transcription and translation that it triggers (not shown).