Abnormal reproductive function in female homozygous leaner mice



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Texas A&M University


The leaner mouse carries an autosomal recessive mutation in the ?1A subunit of neuronal P/Q-type voltage gated calcium ion channels. Due to this mutation, the leaner mouse exhibits severe ataxia, absence seizures and paroxysmal dyskinesia. Mutations in this same gene in humans cause: episodic ataxia type 2, familial hemiplegic migraine, spinocerebellar ataxia type 6 and probably the newly recognized form of human inherited epilepsy. Decreased amplitude of calcium current in cerebellar Purkinje cells and decreased calcium buffering capacity suggest that failure of calcium homeostasis may lead to the neurodegeneration observed in these mutant mice. Both sexes are affected. Despite their neurological dysfunction, homozygous leaner mice are able to breed and produce viable offspring. The survival rate for these pups is highly correlated with early fostering to normal lactating dams.
This thesis studies the reproductive dysfunction observed in female homozygous leaner mice and is divided into four parts: onset of puberty, estrous cycle, pregnancy and litter assessment, and hormone levels. We have discovered that the onset of puberty is precocious in leaner females compared to age-matched wild type females, and leaner mice spend more time in estrous than age-matched wild type females. Also, we have observed that leaner mice became pregnant less readily than wild type mice, but once pregnant, female leaner mice produced more pups per litter compared with wild type mice. The number of corpora lutea observed in leaner mice is greater than in wild type mice. In leaner mice, the number of corpora lutea in the ovary corresponding to the uterine horn with the highest number of offspring is larger than the number of corpora lutea found in the ovary corresponding to the other uterine horn. Radioimmunoassays of estradiol hormone levels at postnatal day 28 shows higher levels in leaner compared to age-matched wild type mice. However, at postnatal day 28, the luteinizing hormone levels are similar in both categories of mice. This study of reproductive dysfunction in leaner mice was performed to gain further understanding about the role of intracellular calcium ion signaling in neuronal regulation of reproductive processes in females.