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The role of cerebellar Kv3.1 and Kv3.3 channels in motor coordination was examined with an emphasis on the deep cerebellar nuclei (DCN). Kv3 channel subunits encoded byKcncgenes are distinguished by rapid activation and deactivation kinetics that support high-frequency, narrow action potential firing. Previously we reported that increased lateral deviation while ambulating and slips while traversing a narrow beam of ataxicKcnc3-null mice were corrected by restoration of Kv3.3 channels specifically to Purkinje cells, whereasKcnc3-mutant mice additionally lacking oneKcnc1allele were partially rescued. Here, we report mice lacking allKcnc1andKcnc3alleles exhibit no such rescue. For Purkinje cell output to reach the rest of the brain it must be conveyed by neurons of the DCN or vestibular nuclei. AsKcnc1, but notKcnc3, alleles are lost, mutant mice exhibit increasing gait ataxia accompanied by spike broadening and deceleration in DCN neurons, suggesting the facet of coordination rescued by Purkinje-cell-restricted Kv3.3 restoration in mice lacking justKcnc3is hypermetria, while gait ataxia emerges when additionallyKcnc1alleles are lost. Thus, fast repolarization in Purkinje cells appears important for normal movement velocity, whereas DCN neurons are a prime candidate locus where fast repolarization is necessary for normal gait patterning.

The mechanisms underlying the formation of the glial scar after injury are poorly understood. In this report, we demonstrate that after cortical injury Olig2 is upregulated in reactive astrocytes coincident with proliferation of these cells. Short-term lineage tracing studies with glial subtype-restricted transgenic reporter lines indicate that Olig2-expressing cells in the astroglial but not the oligodendroglial lineage are the essential source of reactive astrocytes. In addition, corticalOlig2ablation results in a decrease in proliferation of reactive astrocytes in response to injury. Cell-type-specific mutagenesis indicates thatOlig2ablation in GFAP+ astrocytes and their precursors rather than in neuronal or oligodendroglial cells is responsible for the reduction of reactive astrocyte proliferation. Thus, our studies suggest that Olig2 is critical for postinjury gliosis.

The fast-activating/deactivating voltage-gated potassium channel Kv3.3 (Kcnc3) is expressed in various neuronal cell types involved in motor function, including cerebellar Purkinje cells. Spinocerebellar ataxia type 13 (SCA13) patients carrying dominant-negative mutations inKcnc3andKcnc3-null mutant mice both display motor incoordination, suggested in mice by increased lateral deviation while ambulating and slips on a narrow beam. Motor skill learning, however, is spared. Mice lackingKcnc3also exhibit muscle twitches. In addition to broadened spikes, recordings ofKcnc3-null Purkinje cells revealed fewer spikelets in complex spikes and a lower intraburst frequency. Targeted reexpression of Kv3.3 channels exclusively in Purkinje cells inKcnc3-null mice as well as in mice also heterozygous for Kv3.1 sufficed to restore simple spike brevity along with normal complex spikes and to rescue specifically coordination. Therefore, spike parameters requiring Kv3.3 function in Purkinje cells are involved in the ataxic null phenotype and motor coordination, but not motor learning.

Much controversy regarding the anatomical sources of oligodendrocytes in the spinal cord and hindbrain has been resolved. However, the relative contribution of dorsal and ventral progenitors to myelination of the cortex is still a subject of debate. To assess the contribution of dorsal progenitors to cortical myelination, we ablated the basic helix-loop-helix transcription factor Olig2 in the developing dorsal telencephalon. InOlig2-ablated cortices, myelination is arrested at the progenitor stage. Under these conditions, ventrally derived oligodendrocytes migrate dorsally into theOlig2-ablated territory but cannot fully compensate for myelination deficits observed at postnatal stages. Thus, spatially restricted ablation of Olig2 function unmasks a contribution of dorsal progenitors to cortical myelination that is much greater than hitherto appreciated.