Synaptic competition: ‘to be or not to be’ the calyx of Held?

In the dynamic environment of the developing brain, the survival of a chemical synapse appears to follow a simple life principal: to be or not be. The formation of functional networks relies on accurate synapse targeting, formation and endurance, which allow proper connectivity and neurotransmission between neurons. In contrast, synaptic elimination occurs to remove unnecessary and overcrowded connections. Over the past century, dating back to the initial idea by Ramón y Cajal, numerous studies using a variety of model synapses have converged on the prevailing view that activity-dependent synaptic competition is the process in which there can be only one winner among multiple synaptic contacts to stay with the same target. In other words, a strong synapse outcompetes a weak synapse for innervation of the common target and thereby selective connections can be established (Cancedda & Poo, 2009). Synapses are initially formed in excess during development, although it is not clear why, and their competition and elimination ensures the survival of necessary connections in an activity-dependent manner. Postsynaptic remodelling or retrograde signalling can also help stabilize connectivity. In this issue of The Journal of Physiology, Sierksma et al. (2020) present an elegant study to demonstrate an exception to the rule of synaptic competition in the development of a large auditory synapse. Projections of the globular bushy cells (GBCs), part of the sound localization circuit, give rise to the large nerve terminal known as the calyx of Held, to innervate principal cells in the medial nucleus of the trapezoid body (MNTB) and form a remarkable morpho-functional continuum to convey a broad spectrum of information (Yu & Goodrich, 2014; Fekete et al. 2019). GBC axons reach and contacts MNTB cells in mouse embryos at E17 and gradually form premature calyces that are functional at P2. In neonatal age <P4, the MNTB is innervated by multiple calyces that have variable strengths and contact area size (Hoffpauir et al. 2006; Holcomb et al. 2013). It has been proposed that as the rodent develops, one of the stronger and larger calyces outcompetes weaker and smaller nerve endings, and eventually dominates to form one-to-one connectivity by P9. The morphological finding of multiple calyces at the same MNTB neuron and dual evoked response, although rare, lends support to the idea that the GBC terminals compete during development. Morphological analysis alone cannot quantify synaptic strengths although attempts have been made by evaluating the density of the active zones. On the other hand, functional results from slice recordings are open to alternative interpretation since some inputs are lost during slice cutting. With these experimental constraints, direct evidence for or against synaptic competition during the development of the calyx of Held–MNTB synapse in vivo remains elusive. Sierksma et al. (2020) provide novel and direct evidence that the transition from polyneuronal innervation to mono-innervation does not necessarily involve synaptic competition. They combined in vivo measurements from MNTB neurons and immunolabelling in P2–P8 rats to correlate synaptic strength and structure during development. Evoked postsynaptic potentials (EPSPs) from the MNTB were first sorted according to their rate-rise time in order to distinguish between weak and strong inputs. Next, to quantify plausible competition from different inputs, they calculated the ratio between the two strongest EPSPs during development. Surprisingly, the strong input increased from P2 to P8 but not at the cost of the weak input. This finding argues against a model in which the two inputs compete. On the morphological aspect, Sierksma and colleagues visualized the active release sites from the terminals by combining VGlut and Piccolo immunostaining at as early as the P2 age. Importantly, they showed that the size of a VGlut cluster and the EPSP strength are positively correlated. This has not been directly shown before and demonstrates how the increase in synaptic strength during development is related to the growth and cupping of the calyx around the principal cell. Finally, the authors asked whether multiple VGlut clusters represent innervation by multiple calyces. Hence, they calculated the relative occupancy of the largest VGlut cluster and plotted it against the competition ratio of the two strongest EPSPs. Relative occupancy and the competition ratio showed a negative correlation, and no cells were observed where equal competition coincided with 50% VGlut occupancy. Therefore, they concluded that calyceal competition during development is not evident in vivo. The presence of multiple calyces on the same MNTB neuron is undeniable (Holcomb et al. 2013) and therefore the fundamental question of why synaptogenesis is excessive in early development is puzzling. This study by Sierksma et al. (2020) builds a different conceptual paradigm about how synaptic connections are established. Unlike the classical synaptic competition model (Cancedda & Poo, 2009), a synaptic domination model proposed in this study suggests that a weak synapse persists independently of the larger and stronger synapse (Fig. 1). However, it remains unknown when and how weak synapses are eventually eliminated or withdrawn. Competing ideas derived from snapshots of morphological and functional studies are provocative but inconclusive. Therefore, future longitudinal studies in which real-time morpho-functional remodelling of the same synapses in vivo remain a prerequisite. Ultimately, the aim is to resolve the key molecular players that dictate the fate of developing calyces to be or not to be the fittest one to live. No competing interests declared. Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. L.-Y.W. holds a Tier 1 Canada Research Chair in Brain Development and Disorders, and received funding from the Gouvernement du Canada / Canadian Institutes of Health Research (Institutsde recherche en sant´e du Canada): PJT-159527 PJT-156 439; and Gouvernement du Canada / Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada): Discovery.

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