Cerebellar Plasticity in Health and Disease

textabstractThe cerebellum helps fine-tuning movements by evaluating disparities between intention and action, in order to adjust the execution of movements ‘online’, and to keep movements calibrated in the long term. The cerebellar capacity to store information, which provides the ‘memory’ needed for the recalibration of movements, the learning of new motor skills, and associative learning, is provided by modifications in the strength of synaptic couplings between neurons in the cerebellar circuitry (‘synaptic plasticity’). Cerebellar coordination and motor learning can be affected by degenerative processes, such as paraneoplastic cerebellar ataxia (PCA). This is a severe side effect of certain forms of cancer, usually characterized by the degeneration of Purkinje cells, which provide the sole output of the cerebellar cortex. PCA is associated with the expression of antineuronal autoantibodies. In chapters 2 and 3 we describe two patients with Hodgkin’s disease and PCA associated with a previously undescribed autoantibody against the metabotropic glutamate receptor type 1 (mGluR1). This autoantibody directly interferes with receptor function in vitro, affecting synaptic transmission and spontaneous Purkinje neuronal firing behavior, as well as inhibiting the induction of long-term depression of the parallel fiber to Purkinje cell synapse (PF-LTD), a form of synaptic plasticity widely associated with motor learning. Infusion of these anti-mGluR1 autoantibodies into the cerebellum of mice causes severe, reversible ataxia, indicating that PCA autoantibodies can directly affect Purkinje neuronal function by blocking receptors. Post-mortem analysis of one mGluR1-PCA patient’s cerebellum reveals a reduction in the number of Purkinje cells after chronic exposition to anti-mGluR1 autoantibodies. Together these results indicate that the anti-mGluR1 autoantibodies can cause ataxia by acutely interfering with neuronal function and synaptic plasticity, as well as through a chronic degenerative effect on cerebellar Purkinje cells. The block of PF-LTD by the anti-mGluR1 autoantibodies was also shown to affect the patients’ ability to recalibrate motor output. Cerebellar motor learning in the patients was assessed using a saccade adaptation paradigm, in which the amplitude of voluntary fast eye movements (‘saccades’) is gradually changed by systematically displacing a target during a series of consecutive saccades. Although their saccade performance was within the normal range, the capability to gradually adapt saccade amplitude was impaired in the patients with anti-mGluR1 autoantibodies, adding to the body of evidence that PF-LTD underlies forms of motor learning. In chapter 4, further analysis of saccade adaptation characteristics in humans indicates that this form of motor learning conforms to learning rules similar to those of cerebellar synaptic plasticity processes. The time course of induction and the error-based character of saccade adaptation are in line with the properties of cerebellar synaptic plasticity forms, such as PF-LTD. In chapters 5 and 6, the cellular mechanisms putatively underlying cerebellar motor learning were further explored by studying synaptic plasticity in vitro. PF-LTD can be induced by coactivation of parallel fiber (PF) and climbing fiber (CF) input at low frequencies, and is expressed as a reduction in AMPA glutamate receptors on the postsynaptic membrane. This selectively decreases the effect of glutamate released by the PFs that were concurrently active with the CF. In order to prevent synapse saturation and to allow reversal of motor learning, this reduction of PF-Purkinje cell synaptic strength must be counterbalanced by a form of potentiation that is also expressed postsynaptically. This modification, called long-term potentiation of the PF – Purkinje cell synapse (PF-LTP), can be induced by tetanizing only the PF at low frequencies. CF¬evoked calcium transients into the Purkinje cell are shown to be the polarity switch factor making the difference between PF-LTD and PF-LTP induction. Long-term depression of synaptic strength can also be induced at the CF – Purkinje cell synapse (CF-LTD), by high-frequent CF activity. CF-LTD reduces the amplitude of the CF¬evoked calcium transient, which is shown to inhibit the induction of PF-LTD. The concept arises that the cerebellar circuitry uses multiple interacting mechanisms to calibrate its output