Over-expression of parvalbumin in transgenic mice rescues motoneurons from injury-induced cell death

Abstract

Abstract-Following nerve injury in neonatal rats, a large proportion of motoneurons die, possibly as a consequence of an increase in vulnerability to the excitotoxic effects of glutamate. Calcium-dependent glutamate excitotoxicity is thought to play a significant role not only in injury-induced motoneuron death, but also in motoneuron degeneration in diseases such as amyotrophic lateral sclerosis (ALS). Motoneurons are particularly vulnerable to calcium influx following glutamate receptor activation, as they lack a number of calcium binding proteins, such as calbindin-D 28k and parvalbumin. Therefore, it is possible that increasing the ability of motoneurons to buffer intracellular calcium may protect them from cell death and prevent the decline in motor function that usually occurs as a consequence of motoneuron loss. In this study we have tested this possibility by examining the effect of neonatal axotomy on motoneuron survival and muscle force production in normal and transgenic mice that overexpress parvalbumin in their motoneurons.The sciatic nerve was crushed in one hindlimb of newborn transgenic and wildtype mice. The effect on motoneuron survival was assessed 8 weeks later by retrograde labelling of motoneurons innervating the tibialis anterior muscle. Following nerve injury in wildtype mice, only 20.2% (؎2.2, S.E.M.; n‫)4؍‬ of injured motoneurons survive long term compared with 47.2% (؎4.4, S.E.M.; n‫)4؍‬ in parvalbumin overexpressing mice. Surprisingly, this dramatic increase in motoneuron survival was not reflected in a significant improvement in muscle function, since 8 weeks after injury there was no improvement in either maximal twitch and tetanic force, or muscle weights.Thus, inducing spinal motoneurons to express parvalbumin protects a large proportion of motoneurons from injuryinduced cell death, but this is not sufficient to restore muscle function.

Dysregulation of intracellular calcium homeostasis is responsible for neuronal death in an experimental model of selective hippocampal degeneration induced by trimethyltin

“…All above commented data are consistent with the possibility that hippocampal neuronal death is mediated by TMTinduced intracellular Ca 2+ overload activating apoptotic pathways. The hypothesis that Ca 2+ -binding proteins such as CR which play a protective role against cell-deathinducing Ca 2+ overload has also been advanced in a series of neuropathological conditions including amyotrophic lateral sclerosis, ischaemia, AD and Parkinson's disease (Alexianu et al 1994;Mouatt-Prigent et al 1994;Yenari et al 2001;Attems et al 2008;Mattson 2007), and in experimental models of brain injury (Isaacs et al 1997;Dekkers et al 2004;Sasaki et al 2006), although this hypothesis has not been conclusively demonstrated. It is noteworthy in this respect that in the present experimental conditions CR-containing cells do not show signs of early commitment to death as indicated by experiments of doublelabelling for CR and annexin V.…”

Hypoglossal motor neurons display a reduced calcium increase after axotomy in mice with upregulated parvalbumin

“…40% survive if the surgery is made during the first postnatal week (Snider and Thanedar, 1989). In the spinal cord of newborn animals, whereas avulsion or crush of the sciatic nerve produces a 73-80% loss of lumbar motor neurons (Schmalbruch, 1984;Koliatsos and Price, 1996;Dekkers et al, 2004), axotomy of the same nerve In the hypoglossal nucleus of the PVþ/þ animals, numerous stained cellular profiles are visible, which, according to their size, shape, and distribution, can be considered as motor neurons (A). In the hypoglossal nucleus of the B6/SJL mice only background staining can be seen (B).…”

Intracellular Ca2+Regulates Free-Running Circadian Clock OscillationIn Vivo

“…This indicates that PV is an effective tool for modifying the dynamics of intracellular Ca 2ϩ signals in transgenic fly neurons without nonspecifically harming them or abolishing synaptic communication. Indeed, PV has been used in transgenic mice as a protective agent that prevents cytotoxicity and neuronal cell death in the following contexts: a transgenic model of amyotrophic lateral sclerosis, pharmacologically induced excitotoxicity, and physical injury to motoneurons (Beers et al, 2001;Van Den Bosch et al, 2002;Dekkers et al, 2004).…”