Synaptic input as a directional cue for migrating interneuron precursors

Abstract

During CNS development, interneuron precursors have to migrate extensively before they integrate in specific microcircuits. Known regulators of neuronal motility include classical neurotransmitters, yet the mechanisms that assure interneuron dispersal and interneuron/projection neuron matching during histogenesis remain largely elusive. We combined time-lapse video microscopy and electrophysiological analysis of the nascent cerebellum of transgenic Pax2-EGFP mice to address this issue. We found that cerebellar interneuronal precursors regularly show spontaneous postsynaptic currents, indicative of synaptic innervation, well before settling in the molecular layer. In keeping with the sensitivity of these cells to neurotransmitters, ablation of synaptic communication by blocking vesicular release in acute slices of developing cerebella slows migration. Significantly, abrogation of exocytosis primarily impedes the directional persistence of migratory interneuronal precursors. These results establish an unprecedented function of the early synaptic innervation of migrating neuronal precursors and demonstrate a role for synapses in the regulation of migration and pathfinding.

Molecular layer interneurons shape the spike activity of cerebellar Purkinje cells

“…The establishment of these distributions could also be altered in our genetic deletion paradigms. During development, synaptic activity controls the speed and direction of migration 77 . Because stellate cells and basket cells have intra- and inter-cellular connections with one another 34 , loss of GABAergic neurotransmission could impede neuronal migration.…”

Purkinje cell neurotransmission patterns cerebellar basket cells into zonal modules defined by distinct pinceau sizes

“…Purkinje cell neurotransmission is normally present at the time of basket cell progenitor migration and synaptogenesis (Leto et al, 2016). Interestingly, the migration of the progenitors that give rise to molecular layer interneurons, such as the basket cells, are responsive to neurotransmission, with a portion of these signals potentially arising from Purkinje cells (Wefers et al, 2017). Additionally, on the one hand basket cell pinceau formation and targeting is thought to depend on a gradient of neurofascin186 expression, which in turn is dependent on the expression of axon initial segment (AIS) protein ankyrinG (Ango et al, 2004).…”

Inputs from Sequentially Developed Parallel Fibers Are Required for Cerebellar Organization

“…After they stay at the boundary for some time, they appear to translocate through complex migratory routes, in directions of both radial and tangential migration, toward their final positions in the ML (Weisheit et al, 2006;Cameron et al, 2009). In addition, a recent study showed that blocking synaptic release in the cerebellar slices reduced the displacement, directionality, and speed of migration of MLI precursors (Wefers et al, 2017). In the present study, we found that a blockade of the inputs from PF bundles located in the middle and superficial layers altered the distribution of MLIs.…”