Plasma Membrane Ca²⁺ATPase 2 Contributes to Short-Term Synapse Plasticity at the Parallel Fiber to Purkinje Neuron Synapse

Abstract

Plasma membrane Ca2ϩ ATPase 2 (PMCA2) is a fast, highly effective mechanism to control resting cytosolic Ca 2ϩ and Ca 2ϩ excursions in neurons and other excitable cells. The strong expression of PMCA2 in the cerebellum and the cerebellar behavioral deficits presented by PMCA2Ϫ/Ϫ knock-out mice all point to its importance for cerebellar circuit dynamics. Here, we provide direct functional evidence for the influence of presynaptic PMCA2-mediated Ca 2ϩ extrusion for short-term plasticity at cerebellar parallel fiber to Purkinje neuron synapses. Dramatic structural alterations to the Purkinje neurons in the absence of PMCA2 also suggest a strong influence of this fast PMCA2 isoform for development and maintenance of cerebellar function.

Cytosolic Ca2+ Buffers

“…However, the severely distorted PMCA2 2/2 Purkinje cell morphology (smaller cell body, distorted dendritic tree) may also be a likely cause for the ataxic phenotype (Empson et al 2007). In addition to the identified changes occurring in Purkinje cells of CB-D28k 2/2 PV 2/2 mice, an up-regulation of Ca 2þ extrusion/uptake mechanisms was hypothesized, since the decay of dendritic Ca 2þ signals could be accurately fitted only when applying a two-fold higher Ca 2þ extrusion rate, compared to the rates sufficient to model the Ca 2þ transients in PV 2/2 and WT Purkinje cells (Schmidt et al 2003b).…”

Contribution of plasma membrane Ca2+ATPase to cerebellar synapse function

“…Furthermore, PMCA2 makes molecular interactions within synapse-enriched protein complexes that contain syntaxin 1A, one of the components of the pre-synaptic, calciumdependent release machinery [8] . The molecular and functional Ca 2+ imaging evidence [9] also points to an important contribution from PMCA2 to pre-synaptic PF function in the cerebellum (see below).…”

“…An initial indication that PMCA2 in the PN dendrites is physiologically important came from our findings that the PN dendrites in the PMCA2 -/-mice are stunted [9] , as if they do not fully develop in the absence of progressively increased expression of PMCA2 that normally takes place during cerebellar development [7,23] (in the rat, Figure 1C).…”

The Plasma Membrane Calcium ATPasesand Their Role as Major New Players in Human Disease

“…PMCA2 is strongly expressed in Purkinje cells, and both pharmacological inhibition and genetic ablation of PMCA2 from Purkinje neurons impair dendritic growth (109,342). Furthermore, in addition to the aforementioned hearing loss, PMCA2 null mutant mice display overt cerebellar ataxia apparent 12 days after birth accompanied by a severe inability to maintain balance and reduction in body weight (192).…”