Maturation of Purkinje cell firing properties relies on neurogenesis of excitatory neurons

Preterm infants that suffer cerebellar insults often develop motor disorders and cognitive difficulty. Excitatory granule cells, the most numerous neuron type in the brain, are especially vulnerable and likely instigate disease by impairing the function of their targets, the Purkinje cells. Here, we use regional genetic manipulations and in vivo electrophysiology to test whether excitatory neurons establish the firing properties of Purkinje cells during postnatal mouse development. We generated mutant mice that lack the majority of excitatory cerebellar neurons and tracked the structural and functional consequences on Purkinje cells. We reveal that Purkinje cells fail to acquire their typical morphology and connectivity, and that the concomitant transformation of Purkinje cell firing activity does not occur either. We also show that our mutant pups have impaired motor behaviors and vocal skills. These data argue that excitatory cerebellar neurons define the maturation time-window for postnatal Purkinje cell functions and refine cerebellar-dependent behaviors.
eLife digest Preterm infants have a higher risk of developing movement difficulties and neurodevelopmental conditions like autism spectrum disorder. This is likely caused by injuries to a part of the brain called the cerebellum. The cerebellum is important for movement, language and social interactions. During the final weeks of pregnancy, the cerebellum grows larger and develops a complex pattern of folds. Tiny granule cells, which are particularly vulnerable to harm, drive this development. Exactly how damage to granule cells causes movement difficulties and other conditions is unclear. One potential explanation may be that granule cells are important for the development of Purkinje cells in the brain. The Purkinje cells send and receive messages and are very important for coordinating movement. To learn more, van der Heijden et al. studied Purkinje cells in mice during a period that corresponds with the third trimester of pregnancy in humans. During this time, the pattern of electrical signals sent by the Purkinje cells changed from slow and irregular to fast and rhythmic with long pauses between bursts. However, mice that had been genetically engineered to lack most of their granule cells showed a completely different pattern of Purkinje cell development. The pattern of electrical signals emitted by these Purkinje cells stayed slow and irregular. Mice that lacked granule cells also had movement difficulties, tremors, and abnormal vocalizations. The experiments confirm that granule cells are essential for normal brain development. Without enough granule cells, the Purkinje cells become stuck in an immature state. This discovery may help physicians identify preterm infants with motor disorders and other conditions earlier. It may also lead to changes in the care of preterm infants designed to protect their granule cells.