Haploinsufficiency of the E3 Ubiquitin Ligase C-Terminus of Heat Shock Cognate 70 Interacting Protein (CHIP) Produces Specific Behavioral Impairments

The multifunctional E3 ubiquitin ligase CHIP is an essential interacting partner of HSP70, which together promote the proteasomal degradation of client proteins. Acute CHIP overexpression provides neuroprotection against neurotoxic mitochondrial stress, glucocorticoids, and accumulation of toxic amyloid fragments, as well as genetic mutations in other E3 ligases, which have been shown to result in familial Parkinson's disease. These studies have created a great deal of interest in understanding CHIP activity, expression and modulation. While CHIP knockout mice have the potential to provide essential insights into the molecular control of cell fate and survival, the animals have been difficult to characterize in vivo due to severe phenotypic and behavioral dysfunction, which have thus far been poorly characterized. Therefore, in the present study we conducted a battery of neurobehavioral and physiological assays of adult CHIP heterozygotic (HET) mutant mice to provide a better understanding of the functional consequence of CHIP deficiency. We found that CHIP HET mice had normal body and brain weight, body temperature, muscle tone and breathing patterns, but do have a significant elevation in baseline heart rate. Meanwhile basic behavioral screens of sensory, motor, emotional and cognitive functions were normative. We observed no alterations in performance in the elevated plus maze, light-dark preference and tail suspension assays, or two simple cognitive tasks: novel object recognition and spontaneous alternation in a Y maze. Significant deficits were found, however, when CHIP HET mice performed wire hang, inverted screen, wire maneuver, and open field tasks. Taken together, our data indicate a clear subset of behaviors that are altered at baseline in CHIP deficient animals, which will further guide whole animal studies of the effects of CHIP dysregulation on cardiac function, brain circuitry and function, and responsiveness to environmental and cellular stress

The influence of laboratory anaesthetics on the increased cutaneous vascular permeability responses to histamine and 5-hydroxytryptamine in rats

The effect of several anaesthetic regimens on the increased cutaneous vascular permeability response to histamine and 5-hydroxytryptamine (5HT) was investigated in rats, using the Evans blue dye leakage technique. Diethyl ether administered during injections (2–3 minutes) or urethane 1000 mg/kg did not significantly affect responses to either histamine or 5HT compared with responses obtained in rats given no anaesthetic. However ether administered for 10 or 20 minutes significantly increased the response to histamine. All other anaesthetic regimens tested (urethane 1250 mg/kg, urethane-chloralose, urethanepentobarbitone, pentobarbitone, pentobarbitone-xylazine, pentobarbitonechloralose) reduced responses to histamine and/or 5HT. It was concluded that urethane (1000 mg/kg), although it does not produce full surgical anaesthesia, is the most satisfactory alternative to the use of unanaesthetized animals for dye leakage studies in rats