The chemical synapse is a uniquely dynamic structure, and the conversation across it is bidirectional. A retrograde signal (from post-synaptic to pre-synaptic cell) is thought to be important for both the initial development of the synapse (synaptogenesis) and its subsequent modulation by activity(synaptic plasticity). In a pair of papers published in Neuron, a group at Berkeley used an elegant combination of Drosophilatransgenics, electrophysiology and ultrastructure to delineate a retrograde feedback pathway at the Drosophila neuromuscular junction.
The authors' recent work had dealt them a fortunate hand of cards; they knew that mutating either glass bottom boat (gbb, encoding an orthologue of bone morphogenetic protein) or wishful thinking(wit, encoding its receptor) produced grossly deficient synapses,suggesting that they played key roles. Furthermore, they were able to show that wit was expressed presynaptically, and gbbpost-synaptically, in the neuromuscular junction, suggesting that they might signal from post- to presynaptic cells. Other work had also implicated the calcium/calmodulin-sensitive protein kinase, CamKII, in retrograde signalling.
The team modulated the activity of CamKII in the postsynaptic muscle. The effects were clear: there was a small but significant increase in quantal size(the unit of signalling) when CamKII was inhibited, and a decrease when it was overexpressed, suggesting that CamKII in the postsynaptic cell could alter the scale of neurotransmitter release from the presynaptic cell. Consistent with this, the authors observed remodelling of the 'active zone', the region of the presynaptic cell specialised for neurotransmitter release; inhibition of CamKII causes the number of 'T-bars' in the active zone to increase, and vice versa. Just as depth charges are lined up on rails on the destroyer's deck, so T-bars line up neurotransmitter vesicles ready for rapid,efficient release. The changes in morphology are thus consistent with the changes in quantal size. This leads to two further questions: how is the CamKII controlled, and how does this intracellular protein kinase get its message back to a different cell?
The first question is easily answered. Camkinases are activated by calcium,and the glutamergic receptor is highly permeable to calcium. But how about the retrograde message? The paper shows that wit mutants (those lacking the bone morphogenetic protein receptor in presynaptic cells) show defects resembling the post-synaptic inhibition of CamKII; that is, this receptor seems to be involved in receiving the retrograde signal. And, in the accompanying paper, the authors show that interfering with the expression of gbb (the ligand) in the post-synaptic cell has the same effect.
Over the years, many retrograde transmitters have been (controversially)proposed, from nitric oxide to cannabinoids; in the insect neuromuscular junction, the retrograde signalling pathway can now be traced rather completely. Calcium entry into the post-synaptic cell activates CamKII and triggers release of gbb into the synaptic cleft; its reception by wit in the presynaptic cell triggers changes in the synaptic architecture that alter the size of future neurotransmission events.