Ectopic parvalbumin expression in mouse forebrain neurons increases excitotoxic injury provoked by ibotenic acid injection into the striatum

Abstract

A neuroprotective role for Ca 2+ -binding proteins in neurodegenerative conditions ranging from ischemia to Alzheimer's disease has been suggested in several studies. A key phenomenon in neurodegeneration is the Ca 2+ -mediated excitotoxicity brought about by the neurotransmitter glutamate. To evaluate the relative ability to resist excitotoxicity of neurons containing the slow-onset Ca 2+ -binding protein parvalbumin (PV), we injected the glutamate agonist ibotenic acid (IBO) into the striatum of adult mice ectopically expressing PV in neurons. Striatal ibotenic acid injection results in local nerve cell loss and reactive astrogliosis. Light microscopic evaluation, carried out after a delay of 2 and 4 weeks, reveals an enlarged and accelerated neurodegenerative process in mice ectopically expressing neuronal PV. Thus, PV is not neuroprotective, it rather enhances nerve cell death. This result implicates that the increase in cytosolic Ca 2+ -buffering capacity in the transgenic mice impairs other systems involved in Ca 2+ sequestration. In addition, ultrastructural morphometric analysis shows that in neurons the mitochondrial volume is reduced in mice ectopically expressing neuronal PV. This is paralleled by a reduction in the amount of the mitochondrial marker enzyme cytochrome c oxidase subunit I (COXI). We conclude that alterations in the Ca 2+ homeostasis present in mice ectopically expressing neuronal PV are more deleterious under excitotoxic stress and largely outweigh the potential benefits of an increased Ca 2+ -buffering capacity resulting from PV.

Deficiency in parvalbumin, but not in calbindin D-28k upregulates mitochondrial volume and decreases smooth endoplasmic reticulum surface selectively in a peripheral, subplasmalemmal region in the soma of Purkinje cells

“…The ectopic expression of PV in transgenic mice (Van Den Bosch et al, 2002) decreases the mitochondria volume density in striatal neurons (Maetzler et al, 2004), a neuron population with a very low percentage of neurons with endogenous PV expression in WT mice. Thus, the regulation of PV and mitochondria volume is operational in both directions.…”

“…Cerebella were dissected and a soluble and particulate fraction was prepared as described (Maetzler et al, 2004). Proteins (50 -75 g) were separated by polyacrylamide gel electrophoresis (SDS-PAGE) and transferred on nitrocellulose membranes using a semi-dry transfer protocol.…”

Endogenous and Exogenous Ca2+ Buffers Differentially Modulate Ca2+-dependent Inactivation of CaV2.1 Ca2+ Channels

“…The similar effects of PV in stimulating Ca 2ϩ feedback of Ca v 2.1 channels and IP 3 Rs may exemplify fundamental mechanisms controlling Ca 2ϩ -dependent activation of other signaling pathways. In addition, the dual potential for PV to act as a passive Ca 2ϩ buffer and a facilitator of intracellular and plasma membrane Ca 2ϩ channels may contribute to the paradox that PV can be neuroprotective from pathological Ca 2ϩ overloads in some neurons (58), but can also exacerbate excitotoxic cell death in others (59,60).…”

Cytosolic Ca2+ Buffers

“…The latter are characterized by high PV expression levels in WT mice. Vice versa, in transgenic mice ectopically expressing PV in striatal neurons (Van Den Bosch et al 2002), a neuron subpopulation normally not expressing PV, the mitochondrial volume is decreased by almost 50% (Maetzler et al 2004). This reduction accounts for the heightened excitotoxic injury provoked by a local injection of ibotenic acid.…”