Postnatal apoptosis in cerebellar granule cells of homozygous leaner (tg la/tg la) mice

Abstract

Leaner mice carry a homozygous, autosomal recessive mutation in the mouse CACNA1A gene encoding the Alpha1A subunit of P/Q-type calcium channels, which results in an out-of-frame splicing event in the carboxy terminus of the Alpha1A protein. Leaner mice exhibit severe ataxia, paroxysmal dyskinesia and absence seizures. Functional studies have revealed a marked decrease in calcium currents through leaner P/Q-type channels and altered neuronal calcium ion homeostasis in cerebellar Purkinje cells. Histopathological studies of leaner mice have revealed extensive postnatal cerebellar Purkinje and granule cell loss. We examined the temporospatial pattern of cerebellar granule cell death in the leaner mouse between postnatal days (P) 10 and 40. Our observations clearly indicate that leaner cerebellar granule cells die via an apoptotic process and that the peak time of neuronal death is P20. We did not observe a significant increase in microglial and astrocytic responses at P20, suggesting that glial responses are not a cause of neuronal cell death. We propose that the leaner cerebellar granule cell represents an in vivo animal model for low intracellular [Ca2+]-induced apoptosis. Since intracellular [Ca2+] is critical in the control of gene expression, it is quite likely that reduced intracellular [Ca2+] could activate a lethal cascade of altered gene expression leading to the apoptotic granule cell death in the leaner cerebellum.

Analysis of Calcium Ion homeostasis and mitochondrial function in cerebellar granule cells of adult Cav 2.1 Calcium Ion channel mutant mice

“…However, CGC death, while decreased at P30 and P40 compared to P20, is still significantly greater than seen in age-matched wild type mice (Lau et al, 2004). During postnatal development, neurodegeneration in leaner mice follows a specific spatial pattern with more cell death observed in anterior lobe as compared to posterior Lau et al, 2004). Based on histological analysis, Herrup and Wilczynski (1982) reported that the size and density of the CGC layer keeps decreasing, and so hypothesized that the cell death is continuous throughout the life of leaner mice.…”

“…The CGC degeneration occurring in homozygous leaner mice is relatively slow, progressive and extensive, beginning shortly after P10 and peaks at P20 (Lau et al, 2004). However, CGC death, while decreased at P30 and P40 compared to P20, is still significantly greater than seen in age-matched wild type mice (Lau et al, 2004).…”

Dystonia and cerebellar degeneration in the leaner mouse mutant

“…Several prior studies have revealed Purkinje cell loss in the leaner cerebellum beginning at 4 weeks of age, peaking at 8-9 weeks of age, and continuing gradually for several months thereafter (Meier and MacPike 1971; Herrup and Wilczynski 1982; Heckroth and Abbott 1994; Lau, Frank et al 2004). Prior to their death Purkinje neurons show strikingly aberrant morphology (Rhyu, Abbott et al 1999) and electrophysiological function (Walter, Alvina et al 2006; Ovsepian and Friel 2008; Ovsepian and Friel 2012).…”

“…Different Cacan1a mutations in rodent models cause a similarly broad array of disorders, including generalized dystonia or ataxia, paroxysmal dystonia, epilepsy and migraine (Meier and MacPike 1971; Doyle, Ren et al 1997; van den Maagdenberg, Pietrobon et al 2004; Raike, Jinnah et al 2005; Tokuda, Kuramoto et al 2007; Shirley, Rao et al 2008). We selected the leaner mutant not because of its relationship to a variety of different disorders, but because it is known to have severe chronic dystonia (Yoon 1969; Meier and MacPike 1971; Doyle, Ren et al 1997) that is associated with abnormal physiological activity and slow degeneration of cerebellar Purkinje neurons (Meier and MacPike 1971; Herrup and Wilczynski 1982; Heckroth and Abbott 1994; Lau, Frank et al 2004; Walter, Alvina et al 2006; Ovsepian and Friel 2008; Ovsepian and Friel 2012). Thus it provides an ideal tool to address questions regarding the relationships between dystonia and cerebellar dysfunction.…”

Alterations in Intracellular Calcium Ion Concentrations in Cerebellar Granule Cells of the CACNA1A Mutant Mouse, Leaner, During Postnatal Development

“…Homozygous leaner mice exhibit cerebellar ataxia and absence epilepsy starting soon after postnatal (P) day 10-12. There is excessive loss of leaner cerebellar granule cells (CGC) starting at P15, which peaks at P20 and continues into adulthood (Lau et al 2004; Bawa and Abbott 2008). Several autosomal dominant human neurological disorders are associated with mutations in the CACNA1A gene including; familial hemiplegic migraine, generalized epilepsy with ataxia, episodic ataxia type 2 and spinocerebellar ataxia type-6.…”