Dendritic receptors made to order

A fundamental property of many synapses in the brain is an ability to modulate their efficacy of transmission in response to incoming signals. Such changes to the efficiency of synaptic transmission could underlie many neuronal processes, including learning and memory. It has been shown that modification of the density and/or subunit composition of neurotransmitter receptors in the postsynaptic (dendritic) membrane is one mechanism by which neurons can modify their synaptic strength. The synthesis and targeting of such receptor proteins to dendritic areas was thought to be exclusively as a result of production of the proteins within the cell body followed by packaging, sorting and timely transportation to the dendritic membrane. However, the findings of Kacharmina et al. 1xStimulation of glutamate receptor protein synthesis and membrane insertion within isolated neuronal dendrites. Kacharmina, J.E. et al. Proc. Natl. Acad. Sci. USA. 2000; 97: 11545–11550Crossref | PubMedSee all References show that, not only can neurotransmitter receptors be synthesized inside the dendrites and inserted into the membrane, but that this process is pharmacologically sensitive.The production of a transmembrane protein was thought to necessitate the complete machinery of cellular protein synthesis, as found in the cell body. Although parts of this machinery have been identified in dendrites, and protein synthesis is known to occur there, the presence of everything needed for membrane protein synthesis in dendrites was controversial. Kacharmina et al. addressed this problem by expressing neurotransmitter receptors in mechanically isolated dentrites. Rat hippocampal neurons were cultured on coverslips and their dendrites were severed using a microelectrode. The remaining cell body was removed by aspiration to leave an intact set of dendrites on the coverslip. The investigators then liposomally transfected mRNA encoding either an N- or C-terminal cMyc-tagged glutamate receptor (GluR2) into the dendrites and showed that this receptor was successfully synthesized in the severed dendrites. The N-terminus of AMPA glutamate receptors is known to be extracellular, thus demonstration that the cMyc epitope of the N-terminally tagged GluR2 is externally located would show that the protein was integrated into the dendritic membrane which is a prerequisite for functionality in this class of receptors. The investigators achieved this by immunolabeling the N-terminal GluR2 cMyc epitope on transfected dendrites without permeabilizing the plasma membrane, indicating that the N-terminus of the GluR2 is translocated to the extracellular milieu. Finally, the investigators showed that dendritic GluR2 synthesis could be stimulated by DHPG, a metabotropic glutamate receptor agonist. In the absence of DHPG, GluR2 expression in the transfected dendrites was low to negligible, however DHPG application dramatically increased receptor expression in the severed dendrites.The results presented in this paper show that neuronal dendrites have the capacity to autonomously direct transmembrane receptor synthesis in response to external stimuli. Whether this synthesis is via a conventional ER-Golgi-sorting pathway that is self-contained in the dendrite, or via a novel mechanism is unknown. However, the finding that individual dendrites can locally synthesize neurotransmitter receptors has significant implications for our understanding of many neuronal processes. This mechanism could explain how individual synapses are selectively strengthened, by modification of their ‘receptor repertoire’ in response to the activity of their specific pre-synaptic input. A few questions remain to be answered, such as whether dendritic membrane protein synthesis occurs in vivo, and if the dendritically synthesized receptors are indeed functional. However, these findings certainly add another arrow to the quiver of mechanisms that may underlie memory processes in the brain.