JOURNAL CLUB: Sticky matters configuring a synapse
Margaret Ho
Tuesday, 18 March 2008 04:47 UTC
Sticky matters configuring a synapse
The human body senses external inputs and responds to these conveyed signals through a complex neuronal network. Sometimes, to probe the complexity, neuroscientists have to think small and focus on the working unit of synaptic transmission, the synapse. Synapses consist of both a presynaptic and postsynaptic compartments, and it is essential for these two compartments to be properly aligned for accurate assembly. Several molecules that mediate trans-synaptic cell adhesion and signaling have been suggested to be essential in maintaining the integrity and the function of synapses. A paper published last year in Neuron by Li et al. described the crucial role of one such molecule, Neurexin, during synaptic transmission in an intact organism, Drosophila melanogaster (available here).
Neurexins are receptors for alpha–latrotoxin, a neurotoxin that triggers massive neurotransmitter release. Unlike mammals, which express three neurexins, there is only one neuroexin gene in Drosophila (Drosophila neurexin, dnrx). Dnrx is expressed in central neurons and is localized in the active zones, as suggested by work conducted in the Drosophila neuromuscular junction (NMJ). Genetic studies on dnrx showed that flies lacking dnrx exhibited abnormal NMJ structures and reduced synaptic bouton numbers, suggesting that dnrx is involved in NMJ expansion and synapse formation. Moreover, elevated dnrx expression in neurons, but not in muscle, increased synaptic bouton numbers, suggesting that dnrx expression is required for the proliferation of synaptic boutons in the pre-synaptic compartment.
How does dnrx regulate synapse formation and development in vivo? Experimental results provided by Li et al. have nicely addressed this question. First, the authors found that for dnrx mutant synapses, both the distribution of pre-/post-synaptic proteins and the active zone structure were altered. The number of T bars (part of the NMJ active zone structure) per bouton was increased, and both the presynaptic density (PRD) and the postsynaptic density (PSD) were over 60% longer. Defects in mutant dnrx synaptic ultrastructure correlated with synaptic transmission defects, as monitored using electrophysiology. These results suggested that dnrx regulates synaptic formation and development for proper synaptic transmission.
Similar to observations in mammals, flies lacking dnrx abnormally sensed calcium levels, but the distribution of presynaptic calcium channels was unchanged. This suggested that neurexins regulate the coupling between calcium channels and neurotransmitter release machinery. Most strikingly, although the PRD and PSD of dnrx mutant synapses were properly aligned, the PRD exhibited signs of detachment from the PSD at several points. A lack of dnrx had resulted in an adhesion defect between the pre- and postsynaptic cells, causing disruptions in normal synapse formation and function.
Thus, this study has established an in vivo role for neurexin in defining synaptic architecture and providing for proper synaptic transmission. Future work on identifying and characterizing Drosophila neurexin partners will help to elucidate the in vivo function of neurexin.
Discussion Questions:
1) It is known that Drosophila NMJs can compensate for decreased postsynaptic responses by upregulating neurotransmitter release, a potential caveat for interpreting the results here. Have those concerns been properly addressed in this manuscript?
2) Does studying neurexin function in Drosophila provide particular advantages over studying neurexin in mammals?
3) What experiments could have strengthened the evidence suggesting the potential functional interactions between neurexin, Ca2+ channels and neurotransmitter release?
Updated 18 March 2008 04:50 UTC
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Replies
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I think that there still needs to be more work done to fully understand the electrophysiology results. The authors observed an increase in mini-end-plate potential frequency when recording from the muscle cells. Although suggested, it is difficult to say that vesicle release was affected.
With the adhesion between the two sides of the synapse being disrupted, and with the abnormally enlarged arrangement of glutamate receptors in the muscle end-plates, it is also plausible to suggest that vesicle release may be normal, but that glutamate may diffuse further from the PSD because of the defect in junction adhesion. This drifting glutamate could activate receptors aberrantly located outside the normal synaptic zone, providing for the increase in mini frequency. This situation is also consistent with the observed decrease in evoked potential amplitude, possible due to a reduction in the amount of glutamate traversing the cleft, as a result of this increased spillover and diffusion.
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Dear Noah:
Thanks for raising a different perspective on the model provided by this paper. I agree with you that whether or not the vesicle release is affected remain to be determined, nonetheless, the defect in adhesion between PRD and PSD must somehow block (?) the passage of the glutamate and
result in abnormalities in the electrophysiological measures. The authors think that the enlargement of the GluR clusters in PSD is an indication of the NMJs trying to compensate for the cell adhesion defects in order to achieve normal neuronal transmission. Moreover, number of T bars per bouton remains constant, suggesting that though the synaptic bouton number is reduced in the absence of neurexin, the number of T-bar (represent the active zone) increases in the PSD for compensating the potential loss of synaptic transmission resulted from the reduction in the synaptic bouton number. Of course, one cannot rule out the possibility you mentioned, that the glutamate drifts and activates addition receptors.
It would be interesting to look into the details on the vesicle release by some other experiments. Maybe more EM?
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