INTRINSIC CEREBELLAR ACTIVITY MODULATES EARLY NEOCORTICAL MATURATION

Early cerebellar dysfunction is strongly linked to a broad spectrum of neurodevelopmental disorders (NDDs). These disorders are thought to arise from secondary alterations in extracerebellar regions, particularly the neocortex, which supports many behavioral alterations found in NDDs. Yet whether and how the developing cerebellum shapes neocortical maturation during initial circuit formation remains largely unknown.
We identify robust anatomical and functional connectivity between the cerebellum and neocortex early in postnatal development, when long-range circuits are actively assembling, indicating that the cerebellum is poised to influence neocortical development. Consistent with this engagement, structural lesions of the cerebellum during this window induce alterations in cortical spontaneous activity and activity-dependent cortical developmental programs, revealing a previously unappreciated vulnerability of this region to early cerebellar dysfunction.
Because cerebellar–cortical interactions form bidirectional, closed-loop circuits, these phenotypes could reflect both anterograde and retrograde mechanisms. To test whether lesion-induced alterations reflect a loss of instructive cerebellar signals, we asked whether the cerebellum serves as an endogenous source of spontaneous activity capable of guiding cortical maturation. The developing cerebellum generates robust spontaneous activity patterns, driven mainly by excitatory cerebellar nuclei (CN), consistent with their role as principal efferent pathway to the neocortex. Selective disruption of CN intrinsic activity recapitulates most of the functional and molecular cortical phenotypes induced by lesions. These findings identify intrinsic CN activity as a fundamental instructive signal for neocortical maturation and establish the cerebellum as an active builder of cortical circuits, providing a mechanistic framework linking early cerebellar dysfunction to NDDs.