Abstract
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.
Highlights
Abnormal cerebellar development instigates motor diseases and neurodevelopmental disorders including ataxia, dystonia, tremor, and autism
To test the hypothesis that granule cell neurogenesis is essential for the functional development of Purkinje cells, we first established a model of agranular mice that is not initiated by the cellautonomous development of Purkinje cells
Atoh1 is necessary for the development of granule cells, the most populous cell type in the cerebellum, but Atoh1 null mice are neonatal lethal (Ben-Arie et al, 1997)
Summary
Abnormal cerebellar development instigates motor diseases and neurodevelopmental disorders including ataxia, dystonia, tremor, and autism. Purkinje cells are the sole output of the cerebellar cortex and integrate input from up to two hundred fifty thousand excitatory granule cell synapses (Huang et al., 2014), though the predominant Purkinje cell action potential called the simple spike, is intrinsically generated (Raman and Bean, 1999) In this context, it is intriguing that genetically silencing granule cells caused modest alterations to the baseline firing properties of Purkinje cells and impaired only the finer aspects of motor learning, but not gross motor control (Galliano et al, 2013). The discordance between the phenotypes in mutant mice with lower granule cell numbers and mice lacking granule cell function questions whether granule cell neurogenesis, rather than granule cell synaptic signaling, drives the maturation of Purkinje cell firing in vivo
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