The metamorphosis of the developing cerebellar microcircuit

Abstract

The cerebellar cortical circuit with its organized and repetitive structure provides an excellent model system for studying how brain circuits are formed during development. The emergence of the mature brain requires that appropriate synaptic connections are formed and refined, which in the rodent cerebellum occurs primarily during the first three postnatal weeks. Developing circuits typically differ substantially from their mature counterparts, which suggests that development may not simply involve synaptic refinement, but rather involves restructuring of key synaptic components and network connections, in a manner reminiscent of metamorphosis. Here, we discuss recent evidence that, taken together, suggests that transient features of developing cerebellar synapses may act to coordinate network activity, and thereby shape the development of the cerebellar microcircuit.

Figure 1

Metamorphosis of the cerebellar cortical circuit. The developing cerebellar circuit undergoes dramatic changes during postnatal development. Major components of the cerebellar circuit are illustrated at different developmental stages, corresponding to (a) postnatal week 1, (b) postnatal week 2, and (c) adult in rodent. A similar developmental sequence has been observed for some circuit elements in other species, but the time course differs. PCs (orange) exhibit traveling waves in the first postnatal week (illustrated by orange colour gradient in a), make synapses onto other PCs in early development (a), which are reduced in number by postnatal week 2 (b), and absent in adult. PCs receive multiple somatic CF inputs (green) in the first postnatal week, with one winner CF innervating the dendrites by the second postnatal week, with at least 1 weaker somatic inputs remaining (b). Monoinnervation of PCs by CFs is seen in adult (c). Granule cells (blue) migrate from the EGL, to the IGL during the first (a) and second (b) postnatal week. MLIs (purple) innervate PCs and each other in the second postnatal week (b), and in the adult (c). Golgi cells (red) exhibit gap-junction coupling in the adult (c), although possibly earlier as well (not shown).

Figure 2

Postnatal timeline of circuit metamorphosis. Multiple changes occur in the developing cerebellar circuit involving both up-regulation and down-regulation of synaptic elements and the formation and elimination of connections. The timelines of the circuit alterations discussed in this review are shown here, with developmental time on the X-axis. Each vertical bar represents ∼1 postnatal week in rodents, separated by a double line from the adult profile. Red = present, cream = absent, and blue = unknown.

Figure 3

Traveling waves mediated by transient Purkinje–Purkinje cell synapses. During the first postnatal week, PC activity is coordinated to produce traveling waves moving from the tip of the lobule towards its base (illustrated by orange gradient). (a) Image from young animal (P4) showing location of recording electrodes. Scale bar: 50 μm. (b) Traces showing wave-like activity across PCs recorded from neurons indicated in (a). Scale bars: 1 nA (top trace), 100 pA (bottom two traces) and 100 ms. (c) Schematic illustration showing how individual waves travel down each lobule from apex to base. Adapted from Ref. [6^••].