Early dating influences long‐term synaptic partnerships

The formation of neural circuits is the end result of numerous but exquisitely timed and carefully orchestrated cellular and molecular events. Neurons project their axons, sometimes from relatively far distances, to specific regions of the brain where they encounter a number of potential postsynaptic partners and remarkably form stable connections with only a select few. How such cellular specificity occurs has fascinated and puzzled neuroscientists for over a century. Although several mechanisms derived from a wide variety of species and models have been implicated (Sanes & Yamagata, 2009), the concomitant maturational processes that occur in the presynaptic terminals and postsynaptic neuron just prior to their synapse formation and up to functional maturity remain unclear. Most neurons are innervated by hundreds of presynaptic terminals that originate from highly branched axons from distinct cell types located in different brain regions. This complexity, which characterizes most mammalian circuits, presents a formidable experimental challenge; how does one map out the intrinsic maturational events of single neurons and correlate this to the developmental events occurring in an identifiable group of incoming afferents as their synapses are forming. In this issue of The Journal of Physiology, Hoffpauir et al. (2010) take advantage of a rare instance where the organization of a neural circuit makes this possible. Globular bushy cells of the ventral cochlear nucleus (VCN) give rise to axons which project along the ventral border of the brainstem, cross the midline and make a one-to-one connection with the soma of a principle cell of the contralateral medial nucleus of the trapezoid body (MNTB) via a large glutamatergic terminal termed the calyx of Held. The calyx of Held–MNTB synapse is part of the auditory brainstem circuit involved in sound localization, and for nearly two decades neuroscientists have used this model synapse to unravel key mechanisms of synaptic transmission (Schneggenburger & Forsythe, 2006; Wang et al. 2009). Hoffpauir and colleagues have now used this preparation to provide a highly descriptive account of several synchronous biophysical and anatomical events that occur during the early stage of contact between presynaptic terminals and postsynaptic neurons by not only employing traditional slice, electrophysiological and Ca2+ imaging methods, but also combining these with a novel head slice preparation in embryonic mice which preserves the cochlea, the VCN and the MNTB in a single slice maintaining even the most delicate long-distance connections. Principle MNTB neurons are well known to receive minor inputs from conventional synapses in addition to a large calyceal input. Hoffpauir and colleagues demonstrate that by embryonic day 17 (E17), the age at which the MNTB becomes a discernable nucleus, principle neurons are innervated by multiple minor inputs (∼200 pA) (Fig. 1). However by postnatal day 2 (P2), larger inputs become apparent and by P4, one input seemingly dominates and delivers up to several nanoamps of current. It is unclear whether the multiple inputs originate from the same axon as previously reported (Rodriguez-Contreras et al. 2006). This period between P2 and P4 is notable as it coincides with the early development of the calyx of Held terminal from the protocalyx at P2 to the cup-shaped calyx at P4 as demonstrated with three-dimensional rendering of confocal images. While this developmental plasticity is taking place in the presynaptic terminals between E17 and P4, Hoffpauir and colleagues also describe a number of functional events taking place in principle MNTB neurons. In response to step current injections, the discharge patterns of principle MNTB neurons transition from tonic to phasic mode which could be explained in part by the increased expression of low-threshold K+ channels. Coincidently, the resting membrane potential and the input resistance are declining and, not surprisingly, the current threshold to generate action potentials in MNTB neurons is increasing. These developmental changes level off around P4, about 1 week prior to hearing onset in mice. Figure 1 Early maturational events during the formation of the calyx of Held–MNTB synapse The synaptic activity from multiple minor inputs which is present days before calyx growth suggests that some form of activity-driven communication may be part of the developmental programme to select the winning calyceal input. Because MNTB neurons are in a state of hyperexcitability prior to calyx growth (

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