PRRT2-dependent dyskinesia: cerebellar, paroxysmal and persistent

Abstract

In an elegant publication in Cell Research, Tan and colleagues showed that ablation of PRRT2 in cerebellar granule cells is sufficient to induce paroxysmal kinesigenic dyskinesia. PRRT2 turns out to downregulate the presynaptic SNARE complex in granule cell axons, which in turn controls the activity patterns of Purkinje cells, the sole output of the cerebellar cortex.

Figure 1

Potential cerebellar circuit mechanism contributing to PRRT2-dependent dyskinesia. The Purkinje cells (PCs) in the cerebellar cortex (Cbx) inhibit neurons in the cerebellar nuclei (CN), which in turn excite the thalamus (Th) and its networks with the cerebral cortex (Cx) and basal ganglia (BG) (left panel). The axons of the neurons in the cerebellar nuclei (CNN), which can drive motor behavior via these networks, provide recurrent nucleo-cortical fibers (NCF) innervating the granule cell layer in the cerebellar cortex (middle panel). This innervation may contribute to long-term changes in activity of the granule cells (GCs), which in turn modulate the PCs via their parallel fibers (PFs). As shown in the recent paper by Tan and colleagues, the transmission between PFs and PCs can be prominently affected by truncation of PRRT2. Ablation of PRRT2 results in reduced downregulation of the SNARE complex, an increase in docked vesicles and facilitated neurotransmission (right panel top). Upon stimulation, these changes in PF to PC transmission may lead to highly irregular cerebellar cortical and nuclear output (right panel bottom). Thus, once this activity in both the PCs and CNNs is aberrant, it may persist for long periods because of NCFs, generating a pathological reverberating loop prolonging the dyskinesia. Please note that the PC and CNN data in the right bottom panel were not recorded simultaneously and merely serve to exemplify the proposed irregularity; these data were obtained from tottering mice, which sometimes also exhibit similar paroxysmal dyskinesia attacks. The red asterisks above the example of irregular PC activity depict the occurrence of complex spikes. SC indicates the spinal cord, receiving input from Cx.