Purkinje cell ablation and Purkinje cell-specific deletion of Tsc1 in the developing cerebellum strengthen cerebellothalamic synapses

Abstract

Cerebellar damage early in life often causes long-lasting motor, social and cognitive impairments, suggesting the roles of the cerebellum in developing a broad spectrum of behaviours. This recent finding has promoted research on how cerebellar damage affects the development of the cerebral cortex, the brain region responsible for higher-order control of all behaviours. However, the cerebral cortex is not directly connected to the cerebellum. The thalamus is a major direct target of the cerebellar nuclei, conveying cerebellar signals to the cerebral cortex. Despite its crucial position in cerebello–cerebral interaction, thalamic susceptibility to cerebellar damage remains largely unclear. Here, we studied the consequences of early cerebellar perturbation on thalamic development. Whole-cell patch-clamp recordings showed that the synaptic organization of the cerebellothlamic circuit is similar to that of the primary sensory thalamus, in which aberrant sensory activity alters synaptic circuit formation. The ablation of Purkinje cells in the developing cerebellum strengthened cerebellothalamic synapses and enhanced thalamic suprathreshold activities. Purkinje-cell specific deletion of tuberous sclerosis complex subunit 1 (Tsc1), an autism-associated gene for which the protein product negatively regulates the mammalian target of rapamycin, also strengthened cerebellothalamic synapses. However, this strengthening occurred only in homozygous deletion, whereas both homozygous and hemizygous deletion are known to cause autism-like behaviours. These results suggest that, although the cerebellothalamic projection is vulnerable to disturbances in the developing cerebellar cortex, other changes may also drive the behavioural consequences of early cerebellar perturbation.

Key points

• Cerebellar damage early in life often causes motor, social and cognitive impairments, suggesting the roles of the cerebellum in developing a broad spectrum of behaviours.
• Recent studies focus on how the developing cerebellum affects the formation and function of the cerebral cortex, the higher-order centre for all behaviours. However, the cerebellum does not directly connect to the cerebral cortex.
• Here, we studied the consequences of early cerebellar perturbation on the thalamus because it is a direct postsynaptic target of the cerebellum, sending cerebellar signals to the cerebral cortex.
• Loss of cerebellar Purkinje cells, which are commonly associated with various neurological disorders, strengthened cerebellothalamic synapses, suggesting the vulnerability of the thalamus to substantial disturbance in the developing cerebellum.
• Purkinje cell-specific loss of tuberous sclerosis complex-1, a negative regulator of mammalian target of rapamycin, is an established mouse model of autism. This mouse model also showed strengthened cerebellothalamic synapses.