Quantitative trait loci for sensitivity to ethanol intoxication in a C57BL/6J × 129S1/SvImJ inbred mouse cross

Individual variation in sensitivity to acute ethanol (EtOH) challenge is associated with alcohol drinking and is a predictor of alcohol abuse. Previous studies have shown that the C57BL/6J (B6) and 129S1/SvImJ (S1) inbred mouse strains differ in responses on certain measures of acute EtOH intoxication. To gain insight into genetic factors contributing to these differences, we performed quantitative trait locus (QTL) analysis of measures of EtOH-induced ataxia (accelerating rotarod), hypothermia, and loss of righting reflex (LORR) duration in a B6 × S1 F2 population. We confirmed that S1 showed greater EtOH-induced hypothermia (specifically at a high dose) and longer LORR compared to B6. QTL analysis revealed several additive and interacting loci for various phenotypes, as well as examples of genotype interactions with sex. QTLs for different EtOH phenotypes were largely non-overlapping, suggesting separable genetic influences on these behaviors. The most compelling main-effect QTLs were for hypothermia on chromosome 16 and for LORR on chromosomes 4 and 6. Several QTLs overlapped with loci repeatedly linked to EtOH drinking in previous mouse studies. The architecture of the traits we examined was complex but clearly amenable to dissection in future studies. Using integrative genomics strategies, plausible functional and positional candidates may be found. Uncovering candidate genes associated with variation in these phenotypes in this population could ultimately shed light on genetic factors underlying sensitivity to EtOH intoxication and risk for alcoholism in humans

Behavioral Defects in Chaperone-Deficient Alzheimer's Disease Model Mice

Molecular chaperones protect cells from the deleterious effects of protein misfolding and aggregation. Neurotoxicity of amyloid-beta (Aβ) aggregates and their deposition in senile plaques are hallmarks of Alzheimer's disease (AD). We observed that the overall content of αB-crystallin, a small heat shock protein molecular chaperone, decreased in AD model mice in an age-dependent manner. We hypothesized that αB-crystallin protects cells against Aβ toxicity. To test this, we crossed αB-crystallin/HspB2 deficient (CRYAB-/-HSPB2-/-) mice with AD model transgenic mice expressing mutant human amyloid precursor protein. Transgenic and non-transgenic mice in chaperone-sufficient or deficient backgrounds were examined for representative behavioral paradigms for locomotion and memory network functions: (i) spatial orientation and locomotion was monitored by open field test; (ii) sequential organization and associative learning was monitored by fear conditioning; and (iii) evoked behavioral response was tested by hot plate method. Interestingly, αB-crystallin/HspB2 deficient transgenic mice were severely impaired in locomotion compared to each genetic model separately. Our results highlight a synergistic effect of combining chaperone deficiency in a transgenic mouse model for AD underscoring an important role for chaperones in protein misfolding diseases

Effects of NK-4 in a Transgenic Mouse Model of Alzheimer's Disease

Beta-amyloid (Aβ) peptides are considered to play a major role in the pathogenesis of Alzheimer's disease (AD) and molecules that can prevent pathways of Aβ toxicity may be potential therapeutic agents for treatment of AD. We have previously reported that NK-4, a cyanine photosensitizing dye, displays neurotrophic and antioxidant activities. In this study, we report the effects of NK-4 on the toxicity of Aβ and on cognitive function and Aβ concentration in a transgenic mouse model of AD (Tg2576). In vitro, NK-4 effectively protected neuronal cells from toxicity induced by Aβ. In addition, it displayed profound inhibitory activities on Aβ fibril formation. In vivo, Tg2576 mice received an intraperitoneal injection at 100 or 500 µg/kg of NK-4 once a day, five times a week for 9 months. Administration of NK-4 to the mice attenuated impairment of recognition memory, associative memory, and learning ability, as assessed by a novel object recognition test, a passive avoidance test, and a water maze test, respectively. NK-4 decreased the brain Aβ concentration while increasing the plasma amyloid level in a dose-dependent manner. NK-4 also improved memory impairments of ICR mice induced by direct intracerebroventricular administration of Aβ. These lines of evidence suggest that NK-4 may affect multiple pathways of amyloid pathogenesis and could be useful for treatment of AD

Advancing schizophrenia drug discovery : optimizing rodent models to bridge the translational gap

Although our knowledge of the pathophysiology of schizophrenia has increased, treatments for this devastating illness remain inadequate. Here, we critically assess rodent models and behavioural end points used in schizophrenia drug discovery and discuss why these have not led to improved treatments. We provide a perspective on how new models, based on recent advances in the understanding of the genetics and neural circuitry underlying schizophrenia, can bridge the translational gap and lead to the development of more effective drugs. We conclude that previous serendipitous approaches should be replaced with rational strategies for drug discovery in integrated preclinical and clinical programmes. Validation of drug targets in disease-based models that are integrated with translationally relevant end point assessments will reduce the current attrition rate in schizophrenia drug discovery and ultimately lead to therapies that tackle the disease process