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

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Abstract

Leaner mice carry a homozygous, autosomal recessive mutation in the mouse CACNA1A gene encoding the α1A subunit of P/Q-type calcium channels, which results in an out-of-frame splicing event in the carboxy terminus of the α1A 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 anin 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.

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Authors and Affiliations

  1. USDA, HNRCA, Tufts University, 711 Washington St., 02111, Boston, MA, USA

    Francis C. Lau

  2. Department of Veterinary Anatomy and Public Health, College of Veterinary Medicine, Texas A & M University, 4458 TAMU, 77843-4458, College Station, TX, USA

    Tamy C. Frank & Louise C. Abbott

  3. Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A & M University, 4458 TAMU, 77843-4458, College Station, TX, USA

    Gheorghe Stoica

  4. Department of Human Anatomy and Medical Neurobiology, College of Medicine, Texas A&M University System Health Science Center, 1114 TAMU, 77843-1114, College Station, TX, USA

    Sang-Soep Nahm

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  1. Francis C. Lau
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Correspondence to Louise C. Abbott.

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Lau, F.C., Frank, T.C., Nahm, SS. et al. Postnatal apoptosis in cerebellar granule cells of homozygous leaner (tg la/tg la) mice. neurotox res 6, 267–280 (2004). https://doi.org/10.1007/BF03033437

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