• 2019-07
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  • 2021-03
  • Studies on Dys deficient rodent


    Studies on Dys-deficient rodent hippocampal neurons revealed the up-regulation of presynaptic neurotransmitter release [47,48] with accompanying morphological alterations in the presynaptic compartment [49,50], which is consistent with the present results obtained at the Drosophila NMJ. However, a recent study implicated the DGC in a different form of homeostatic plasticity in the mammalian CNS [51]. Since the transmembrane DG protein provides the DGC's anchor in the membrane and its absence results in the delocalization of DGC components, the absence of Dyb may also, at least partially, contribute to this form of homeostatic plasticity. A previous study consistently showed that mice lacking both Dyb isoforms (DTNA and DTNB), but not either alone, displayed a significant reduction in GABAAα1 foci at cerebellar inhibitory synapses [52. However, this homeostatic plasticity differs from our Drosophila NMJ homeostatic studies because we did not observe any morphological or functional changes in the postsynaptic receptor field in DGC mutants (this work and [16,17]). Dyb mutants do not display increased QC when challenged with PhTx. This disruption of presynaptic Lycopene is associated with the failure to modulate the RRP. The failure to modulate the RRP in a RIM mutant background was previously shown to correlate with impaired presynaptic homeostasis [10]. The difference between Dyb and RIM mutations is that the Dyb, but not RIM, mutant displays an increase in presynaptic release at baseline; this effect correlates with an increase in the number of presynaptic active zones. Since the Dyb mutant does not display impaired PPF, we attributed enhanced basal neurotransmitter release to an increase in the active zone number, not a change in release probability. Similarly, we previously demonstrated that Cv-c mutants did not exhibit increased PPF [17] supporting the idea that the DGC-mediated pathway does not regulate the probability of release. The QC elevation can be caused by either increased probability of release or increased RRP size. Our group previously reported that an elevation in evoked neurotransmitter release in Dys mutant was because of an increased probability of release rather than an increased size of RRP [16]. Although Dys and Dyb have been found to interact, the causative of an elevation on evoked neurotransmitter release was likely different. In the present study, Dyb mutant did not increase in probability of release but it showed the defect in the RRP modulation after PhTx administration. However, the methods of RRP determination between these two studies were likely different (this work and [16]), these might affect an interpretation of the results. The restoration of Dyb into a postsynaptic, but not a presynaptic, compartment in the Dys mutant background suppressed the high QC phenotype of the Dys mutant. These results confirmed that the loss of Dyb from the SSR, which is regarded as a postsynaptic compartment, in the Dys mutant background enhanced presynaptic release. Further studies are warranted to more clearly understand how DGC members collaboratively function and, in the case of their dysfunction, affect neurons, muscles, and other tissues. The roles of Dyb in the presynaptic compartment currently remain unclear. However, postsynaptic Dyb appears to be mainly involved in the regulation of bouton numbers, QC, and homeostatic plasticity. We were able to rescue these Dyb mutant phenotypes solely by the postsynaptic expression of Dyb. The significance of Rho signaling in maintaining synaptic function is underscored by the identification of a number of human Rho gene-associated mutations underlying cognitive deficit syndromes [53]. Interestingly, the Rho GTPase Cdc42 has also been shown to play a presynaptic role in homeostasis at the NMJ. It acts downstream of the Eph receptor-binding Ephexin protein as a member of a pathway that modulates presynaptic CaV2.1 channels during the homeostatic enhancement of presynaptic release [43]. Collectively, the present results contribute to elucidating the mechanism of action of the DGC complex in the regulation of neurotransmitter release, which is schematically depicted in Fig. S6, in which the postsynaptic DGC complex at the NMJ organizes Rho-GTPase signaling with effects on both presynaptic neurotransmitter release and presynaptic homeostasis. The present results contribute to a better understanding of the likely evolutionarily conserved postsynaptic roles of the DGC in synaptic homeostasis.