Zonal organization of the mouse flocculus: physiology, input, and output.

The zones of the flocculus have been mapped in many species with a noticeable exception, the mouse. Here, the functional map of the mouse was constructed via extracellular recordings followed by tracer injections of biotinylated-dextran-amine and immunohistochemistry for heat-shock protein-25. Zones were identified based on the Purkinje cell complex spike modulation occurring in response to optokinetic stimulation. In zones 1 and 3 Purkinje cells responded best to rotation about a horizontal axis oriented at 135 degrees ipsilateral azimuth, whereas in zones 2 and 4 they responded best to rotation about the vertical axis. The tracing experiments showed that Purkinje cells of zone 1 projected to the parvicellular part of lateral cerebellar nucleus and superior vestibular nucleus, while Purkinje cells of zone 3 projected to group Y and the superior vestibular nucleus. Purkinje cells of zones 2 and 4 projected to the magnocellular and parvicellular parts of the medial vestibular nucleus, while some also innervated the lateral vestibular nucleus or nucleus prepositus hypoglossi. The climbing fiber inputs to Purkinje cells in zones 1 and 3 were derived from neurons in the ventrolateral outgrowth of the contralateral inferior olive, whereas those in zones 2 and 4 were derived from the contralateral caudal dorsal cap. Purkinje cells in zones 1 and 2, but not in zones 3 and 4, were positively labeled for heat-shock protein-25. The present study illustrates that Purkinje cells in the murine flocculus are organized in discrete zones with specific functions, specific input - output relations, and a specific histochemical signature.

Impairment of LTD and cerebellar learning by Purkinje cell-specific ablation of cGMP-dependent protein kinase I.

The molecular basis for cerebellar plasticity and motor learning remains controversial. Cerebellar Purkinje cells (PCs) contain a high concentration of cGMP-dependent protein kinase type I (cGKI). To investigate the function of cGKI in long-term depression (LTD) and cerebellar learning, we have generated conditional knockout mice lacking cGKI selectively in PCs. These cGKI mutants had a normal cerebellar morphology and intact synaptic calcium signaling, but strongly reduced LTD. Interestingly, no defects in general behavior and motor performance could be detected in the LTD-deficient mice, but the mutants exhibited an impaired adaptation of the vestibulo-ocular reflex (VOR). These results indicate that cGKI in PCs is dispensable for general motor coordination, but that it is required for cerebellar LTD and specific forms of motor learning, namely the adaptation of the VOR.

Mechanisms underlying cerebellar motor deficits due to mGluR1-autoantibodies.

Patients with Hodgkin's disease can develop paraneoplastic cerebellar ataxia because of the generation of autoantibodies against mGluR1 (mGluR1-Abs). Yet, the pathophysiological mechanisms underlying their motor coordination deficits remain to be elucidated. Here, we show that application of IgG purified from the patients' serum to cerebellar slices of mice acutely reduces the basal activity of Purkinje cells, whereas application to the flocculus of mice in vivo evokes acute disturbances in the performance of their compensatory eye movements. In addition, the mGluR1-Abs block induction of long-term depression in cultured mouse Purkinje cells, whereas the cerebellar motor learning behavior of the patients is affected in that they show impaired adaptation of their saccadic eye movements. Finally, postmortem analysis of the cerebellum of a paraneoplastic cerebellar ataxia patient showed that the number of Purkinje cells was significantly reduced by approximately two thirds compared with three controls. We conclude that autoantibodies against mGluR1 can cause cerebellar motor coordination deficits caused by a combination of rapid effects on both acute and plastic responses of Purkinje cells and chronic degenerative effects.