Extensive early motor and non-motor behavioral deficits are followed by striatal neuronal loss in knock-in Huntington's disease mice.

Huntington's disease is a neurodegenerative disorder, caused by an elongation of CAG repeats in the huntingtin gene. Mice with an insertion of an expanded polyglutamine repeat in the mouse huntingtin gene (knock-in mice) most closely model the disease because the mutation is expressed in the proper genomic and protein context. However, few knock-in mouse lines have been extensively characterized and available data suggest marked differences in the extent and time course of their behavioral and pathological phenotype. We have previously described behavioral anomalies in the open field as early as 1 month of age, followed by the appearance at 2 months of progressive huntingtin neuropathology, in a mouse carrying a portion of human exon 1 with approximately 140 CAG repeats inserted into the mouse huntingtin gene. Here we extend these observations by showing that early behavioral anomalies exist in a wide range of motor (climbing, vertical pole, rotarod, and running wheel performance) and non-motor functions (fear conditioning and anxiety) starting at 1-4 months of age, and are followed by progressive gliosis and decrease in dopamine and cyclic AMP-regulated phosphoprotein with molecular weight 32 kDa (DARPP32) (12 months) and a loss of striatal neurons at 2 years. At this age, mice also present striking spontaneous behavioral deficits in their home cage. The data show that this line of knock-in mice reproduces canonical characteristics of Huntington's disease, preceded by deficits which may correspond to the protracted pre-manifest phase of the disease in humans. Accordingly, they provide a useful model to elucidate early mechanisms of pathophysiology and the progression to overt neurodegeneration.

Early behavioral deficits in R6/2 mice suitable for use in preclinical drug testing.

Huntington's disease (HD) is a neurodegenerative disorder caused by an elongated glutamine repeat in huntingtin. Improved understanding of the molecular effects of the mutation opens new avenues for treatment. High-throughput automated behavioral tests that produce well-defined markers of disease progression are necessary for in vivo drug screening. We have identified early behavioral deficits in tests of motor function that are amenable to cost effective automated analysis in a mouse model of HD. Running wheel activity and climbing behavior were reduced in R6/2 HD transgenics from as early as 4.5 weeks of age, at a time when rotarod performance and grip strength were still normal. Power calculations showed that the running wheel test was appropriate for efficient, high-throughput drug screening at this early age. Furthermore, the data extend the range of behavioral deficits observed in 1-month-old R6/2 mice, an age when synaptic dysfunction can already be detected in the striatum.

The use of transgenic and knock-in mice to study Huntington's disease.

The trinucleotide repeat disorders comprise an ever expanding list of diseases, all of which are caused by an unstable expanded trinucleotide repeat tract. Huntington's disease (HD) is a member of this family of diseases and more specifically, is a Type II trinucleotide repeat disorder. This means that the mutation in HD is an unstable expanded polyglutamine repeat tract, which is expressed at protein level. There is no cure or beneficial treatment for this fatal neurodegenerative disorder, and patients suffer from progressive motor, cognitive and psychiatric dysfunction. Recent years has seen the development of many genetic models of HD, which allow study of the early phases of disease process, at several different levels of cell function. In addition, these models are being used to investigate the potential of a variety of therapeutic agents for clinical use. Here we review these findings, and their implication for HD pathogenesis.

Methamphetamine toxicity in mice is potentiated by exposure to loud music.

Methamphetamine (METH) is a drug of abuse used for its stimulant effects. Its neurotoxicity is very variable, and is increased by a number of factors, including crowded conditions and increased ambient temperature. The effects of such factors are increasingly important, with the widespread use of these stimulants at nightclubs and 'raves'. Here, we compared the effect of another dominant feature of nightclubs, continuous loud noise, on the toxicity of METH in mice. We found that mice exposed to loud music exhibited longer lasting stereotypy, an altered place preference in the open field and had more seizures than mice given METH in a quiet setting or when exposed to loud white noise. A greater increase in reactive gliosis was also seen after exposure to METH and loud music. Thus, METH appears to be more toxic when taken while exposed to loud music.

Mice transgenic for the Huntington's disease mutation are resistant to chronic 3-nitropropionic acid-induced striatal toxicity.

Neuronal loss in Huntington's disease (HD) is seen first in the neostriatum. It has been suggested that impaired metabolism underlies this degeneration, as striatal vulnerability to excitotoxicity is increased by metabolic compromise. At 12 weeks of age, a transgenic mouse carrying the HD mutation (R6/2 line) has been shown to have an increased vulnerability to the mitochondrial toxin 3-nitropropionic acid (3-NP). However, in contrast, younger R6/2 mice appear to be less vulnerable than wild-type (WT) mice to the excitotoxins kainic acid and quinolinic acid (QA). In this study, we examine the possibility that the sensitivity of R6/2 mice to 3-NP might be age dependent. We treated young, symptomatic R6/2 mice with 3-NP and found that despite their progressive neurological phenotype, they were not more susceptible to 3-NP intoxication than their WT littermates. Further, fewer R6/2 than WT mice developed striatal lesions. We suggest that compensatory mechanisms exist in the R6/2 mouse brain that protect it against the toxic effect of the transgene and coincidentally protect against exogenous toxins such as 3-NP, QA, and kainic acid. The existence of similar compensatory mechanisms may explain why, in humans, HD is a late-onset disorder, despite early expression of the genetic mutation.

The epidemiology of Plasmodium falciparum malaria in two Cameroonian villages: Simbok and Etoa.

In support of ongoing immunologic studies on immunity to Plasmodium falciparum, demographic, entomologic, parasitologic, and clinical studies were conducted in two Cameroonian villages located 3 km apart. Simbok (population = 907) has pools of water present year round that provide breeding sites for Anopheles gambiae, whereas Etoa (population = 485) has swampy areas that dry up annually in which A. funestus breed. Results showed that individuals in Simbok receive an estimated 1.9 and 1.2 infectious bites per night in the wet and dry season, respectively, whereas individuals in Etoa receive 2.4 and 0.4 infectious bites per night, respectively. Although transmission patterns differ, the rate of acquisition of immunity to malaria appears to be similar in both villages. A prevalence of 50-75% was found in children < 10 years old, variable levels in children 11-15 years old, and 31% in adults. Thus, as reported in other parts of Africa, individuals exposed to continuous transmission of P. falciparum slowly acquired significant, but not complete, immunity.