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Comparative Study
. 2007 Apr 4;27(14):3753-8.
doi: 10.1523/JNEUROSCI.0069-07.2007.

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

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Free PMC article
Comparative Study

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

Ruth M Empson et al. J Neurosci. .
Free PMC article

Abstract

Plasma membrane Ca2+ ATPase 2 (PMCA2) is a fast, highly effective mechanism to control resting cytosolic Ca2+ and Ca2+ excursions in neurons and other excitable cells. The strong expression of PMCA2 in the cerebellum and the cerebellar behavioral deficits presented by PMCA2-/- 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 Ca2+ 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.

Figures

Figure 1.
Figure 1.
PF-evoked EPSCs in PNs from PMCA2−/− mice exhibited enhanced PPF that recovered more slowly than WT PPF. A, PPF of the PF input to PNs from WT (left) and PMCA2−/− (right) mice, at varying ISIs. Traces represent responses averaged over 17 cells. B shows the average PPR as a function of ISI for all cells, WT (filled symbols and lines) and PMCA2−/− (open symbols), where dotted lines show extrapolated values determined from the exponential fits. C shows recovery of amplitude normalized PPR for WT and PMCA2−/− (filled and open symbols and lines, respectively). Recovery of PPR fitted with a double exponential in all cases. The first half-time for PPR decay, T1, increased from 21 to 51 ms and the second, slower half-time for PPR decay, T2, increased from 286 to 650 ms. D shows means from individual recovery phases of PPR (T1 and T2) for WT (filled bars) and PMCA2−/− (open bars). *p < 0.05; **p < 0.01. All values are mean ± SEM.
Figure 2.
Figure 2.
Carboxyeosin, an inhibitor of PMCAs, enhanced PPF of PF-evoked EPSCs in PNs from WT but not PMCA2−/− mice. A, PPF of the PF input to a representative PN from a WT mouse, at varying ISIs, before (left) and after (middle) treatment with 10 μm CE. Note the increase in amplitude of the second and subsequent EPSCs compared with control. The far right panel shows the increase in the average PPR as a function of ISI for all WT cells, before (filled squares) and after treatment with CE (filled triangles) (n = 3). The lines represent double exponential fits to the mean data, and the dotted lines show extrapolated values determined from the exponential fits. CE also slowed the recovery of the PPF in WT cells. The first half-time for PPR decay, T1, in the WT cells increased from 25 to 41 ms, and the second, slower half-time for PPR decay, T2, increased from 102 to 204 ms in the presence of CE. CE application lasted 20 min. B, Results from the same experiment as in A, but from cells from PMCA2−/− mice, where the mean PPF (n = 3; far right) was not further enhanced by the presence of CE (open squares vs open triangles), nor its recovery slowed. The left and middle panels show traces from a representative PMCA2−/− cell. All values are means ± SEM.
Figure 3.
Figure 3.
Recovery of presynaptic PF [Ca2+]i transients was slowed in slices from PMCA2−/− mice. A, PF stimulation-induced presynaptic Ca2+ transients. Top left, Transmission image. Asterisk denotes tip of stimulation electrode. GCL, Granule cell layer. Top right, Resting fluorescence image. Note two dye deposits and resting fluorescence of associated PF bundles. Bottom left, Pseudocolored map of peak ΔF/F signal, the baseline normalized change in fluorescence, induced by a single electrical stimulation of PFs. Bottom right, The time course of the Ca2+ transients extracted from regions of interest (white boxes, bottom left) along the PF bundle “beam”-shaped responsive area. Ca2+ signals are averages >20 stimulations. B, Time course of the average, normalized PF Ca2+ transient for WT (left, in black) and PMCA2−/− (right, in red). Each point represents the average response obtained from n = 6 slices normalized to their peak amplitude determined by double exponential fits (lines). C, Recovery time constants from double exponential fits. Values are mean ± SEM of the individual fast (T1) and slow (T2) time constants of recovery fitted individually to all PF presynaptic Ca2+ transients. **p < 0.01.
Figure 4.
Figure 4.
Purkinje neuron morphology was altered in PMCA2−/− mice. A, representative WT and PMCA2−/− PNs. B, Basic morphological measurements from n = 20 reconstructed cells; mean values ± SEM are *p < 0.05, **p <0.01, and ***p < 0.001.

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