The specific loss of GnRH-positive neurons from the hypothalamus of sheep with CLN6 neuronal ceroid lipofuscinosis occurs without glial activation and has only minor effects on reproduction.

The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are characterized by progressive neurodegeneration resulting in widespread brain atrophy. Each form is assumed to be the consequence of some universal intracellular event; however, time course studies on the cerebral cortex of a sheep model of the CLN6 form revealed distinct regional neurodegeneration preceded by regional glial activation, spreading from quite localized foci. Previous neurological investigations have concentrated on obviously affected cortical functions. This study investigated the impact of ovine CLN6 NCL on a subcortical structure and function, the discrete gonadotrophin-releasing hormone (GnRH) secreting neurons of the hypothalamus, and the effect of changes in the neuroendocrine system on reproductive efficiency and embryonic development. The number of immunopositive GnRH neurons in the hypothalamus and median eminence of affected sheep was reduced by 80%, but the rest of the hypothalamus showed no changes or atrophy. This specific loss of neuron type was not accompanied by either microglial or astrocyte activation, which was absent from the hypothalamus and was not associated with cell-type-specific storage body accumulation. Ovarian responsiveness to follicle stimulating hormone, ovulation rates, sperm production, fertilization rates, embryonic development, and reproductive efficiency were sub-par but reproduction was still functional. This remains when the sheep are profoundly blind. We conclude that physiological functionality and connectivity, not genotype, determine neuron fate in CLN6 NCL. Copyright © 2010 Elsevier Inc. All rights reserved.