Androgen function in the pathophysiology and treatment of male Huntington's disease patients.

Low concentrations of circulating testosterone have been associated with dementia manifesting with advancing age and in neurodegenerative conditions. Huntington's disease (HD) is a dominantly inherited neurodegenerative disease with an invariably fatal outcome. Severe motor symptoms, psychosis and dementia are symptomatic hallmarks of the progression of HD that result from the dysfunction and death of neocortical and basal ganglia neurones. Treatments are directed toward manifest symptoms, although they are largely ineffectual in slowing or preventing disease progression. Emerging data have identified hypothamic pathologies in HD that result in endocrine disturbances. Clinically defined primary or secondary hypogonadism elicit low circulating testosterone concentrations and have been linked to the development of Alzheimer's disease in men. Examining similar neuroendocrine dysfunction in HD including the nature of manifest hypogonadism in male patients could allow an elucidation of the complex pathophysiology of HD and provide an impetus for hitherto untested testosterone replacement therapy.

Deficits in spermatogenesis but not neurogenesis are alleviated by chronic testosterone therapy in R6/1 Huntington's disease mice.

Despite the well established central pathophysiology of Huntington's disease (HD), less is known about systemic impairments that are emerging as significant contributors to the morbidity of this neurodegenerative condition. Given the evidence of neuroendocrine dysfunction in HD patients and the pro-neural properties of sex-hormones, we explored the therapeutic potential of hormone therapy in the HD R6/1 mouse model (HD mice). HD mice over-express exon-1 of the defective human HD gene and replicate many of the clinical behavioural, biochemical and physiological impairments. Seven-week-old HD and wild-type littermate mice had either saline (control) or testosterone (treatment; 160µg/day over 90days) pellets implanted s.c. and were subsequently subjected to behavioural, molecular and cellular analysis. Separate mice were used to establish a decrease in serum testosterone concentrations in HD mice at 12weeks of age. Baseline serum testosterone was significantly reduced in control 19-week-old HD mice, whereas treatment significantly raised serum testosterone in both wild-type and HD mice. Testosterone treatment had a limited effect on the development of rotarod deficiencies in HD mice and no effect on progressive body weight loss or the development of central mutant huntingtin-containing aggregates. Testosterone treatment induced hypo-locomotion in both genotypes. Deficits in hippocampal-dependent cognition and neurogenesis were not rescued in testosterone-treated HD mice. By contrast, wild-type-treatment mice experienced significantly increased neuronal survival and differentiation. Testosterone treatment in HD mice did rescue androgen receptor levels in the hippocampus and testes, significantly improved severe testicular atrophy and restored spermatogenesis. We conclude that chronic testosterone provides systemic efficacy in treating spermatogenesis deficits and testicular atrophy but not central cellular and behavioural pathologies in R6/1 HD mice.

Analysis of neuronal subpopulations in mice over-expressing suppressor of cytokine signaling-2.

Developing an understanding of factors that regulate development of the nervous system is important if we hope to be able to repair the nervous system after injury or disease. Suppressor of cytokine signaling-2 (SOCS2) is an intracellular regulator of cytokine signaling that blocks the inhibitory effects of growth hormone on neuronal differentiation and promotes neurogenesis. Here we examine the effect of SOCS2 over-expression on brain development by assessing density and soma size of different neuronal populations in the somatosensory cortex and striatum of SOCS2 transgenic mice compared with wildtype C57BL/6 mice. There were no significant differences in brain weight, cortical thickness or striatal area between mice of either genotype. Analysis of NeuN positive neuronal cell density showed a modest but significant 9% increase across layers 2-6 of SOCS2 transgenic cortex, while cortical interneuron subpopulations were variably affected. In the cortex, parvalbumin and somatostatin expressing neuron densities were unaffected, while calretinin and calbindin positive neuronal densities increased by 48% and 45% respectively. There was no apparent difference in glial fibrillary acidic protein positive astrocyte numbers in layers 1 or 6b of cortex. Furthermore, soma sizes of calretinin and calbindin positive cortical neurons were significantly smaller than wildtype, although there was no difference in size of Cresyl Violet-stained layer 5 projection neurons nor of parvalbumin or somatostatin positive cortical neurons. Additionally, synaptic density and dendritic branching were found to be increased in SOCS2 transgenic cortex. These effects on calretinin and calbindin positive cortical neurons and cortical neuronal circuitry were not observed in the striatum of SOCS2-Tg brains. However, striatal cholinergic interneurons were significantly smaller in SOCS2-Tg brains. At embryonic day 14.5, proliferation and apoptosis in the developing telencephalon were similar in each genotype. Therefore, over-expression of SOCS2 variably affects different cortical regions and neuronal populations, with the predominant effect appearing to be on interneurons and neuronal connectivity in the cortex.