Functions Of NPC And CPLA2α In Cerebellar Plasticity

Cerebellum is an important part of central nervous system in coordinating movements and keeping balance. The histological structure of cerebellum is quite clear, in which the main output neurons, GABAergic Purkinje cells, receive projections from parallel fibers and climbing fibers. There are enormous connections between one Purkinje cell and many other parallel fibers, which are generally accepted as memory residing places. The proteins and enzymes that affect the PF-PC synapses will affect the physiological function of the cerebellum. Here we studied two gene mutant mouse, NPC and cPLA2a, in order to find out how they change the PF-PC synaptic functions and the potential mechanisms.Niemann-Pick type C disease (NPC) is an autosomal recessive lipidosis characterized by progressive neurodegeneration. Although several studies have revealed unusual accumulation of unesterfied cholesterol in astrocytic lysosome of NPC, pathophysiological basis of cerebellar neuronal dysfunction remains unclear. We compared parallel fiber-Purkinje cell synaptic transmission and long-term depression (LTD) in+/+npcnih (npc+/+) and-/-npcnih (npc-/-) mice. Our data showed that adenosine Al receptor agonists decreased parallel fiber excitatory postsynaptic current (EPSC) amplitude and mEPSC frequency, while its antagonists increased EPSC amplitude and mEPSC frequency in wild type and mutant mice. Furthermore, parallel fiber LTD was deficient in npc-/-mice and supplement of adenosine triphosphate (ATP) rescued the impaired LTD. Taken together, these experiments suggest that synaptic strength and LTD are altered in npc-/-mice due to the decrease of ATP/adenosine release and deactivation of A1receptors in parallel fiber terminals. The enhanced synaptic transmission and the decreased LTD might result in progressive neurotoxicity of Purkinje cells in npc-/-mice.Depolarization-induced suppression of excitation (DSE) at parallel fiber-Purkinje cell synapses is an endocannabinoid-mediated short-term retrograde plasticity. Intracellular Ca2+elevation is critical for the endocannabinoid production and DSE. Nevertheless, what biochemical pathways are evoked by elevated Ca2+and are involved in the synthesis and release of endocannabinoids is not clear. In the present work, we measured DSE at parallel fiber-Purkinje cell synapses in wild-type and cytosolic phospholipase A2alpha(cPLA2a) knock-out mice. Our data showed that DSE was inhibited in cPLA2a knock-out mice, but rescued by bath application of arachidonic acid, which was freed by phospholipase A2. We also showed that DSE at parallel fiber-Purkinje cell synapses was blocked by internal K+, but not affected by antagonists of the purinergic P2X7receptor, PKC and PKA. Together with previous studies, these findings further elucidate the mechanisms by which brief depolarization induces DSE at parallel fiber-Purkinje cell synapses.