Proteasome mapping reveals sexual dimorphism in tissue-specific sensitivity to protein aggregations.

Defects in the proteasome can result in pathological proteinopathies. However, the pathogenic role of sex- and tissue-specific sensitivity to proteotoxic stress remains elusive. Here, we map the proteasome activity across nine tissues, in male and female mice, and demonstrate strong sexual dimorphism in proteasome activity, where females have significantly higher activity in several tissues. Further, we report drastic differences in proteasome activity among tissues, independently of proteasome concentration, which are exacerbated under stress conditions. Sexual dimorphism in proteasome activity is confirmed in a SOD1 ALS mouse model, in which the spinal cord, a tissue with comparatively low proteasome activity, is severely affected. Our results offer mechanistic insight into tissue-specific sensitivities to proteostasis stress and into sex differences in the progression of neurodegenerative proteinopathies.

Chronic early life lead (Pb2+) exposure alters presynaptic vesicle pools in hippocampal synapses.

BACKGROUND: Lead (Pb2+) exposure has been shown to impair presynaptic neurotransmitter release in both in vivo and in vitro model systems. The mechanism by which Pb2+ impairs neurotransmitter release has not been fully elucidated. In previous work, we have shown that Pb2+ exposure inhibits vesicular release and reduces the number of fast-releasing sites in cultured hippocampal neurons. We have also shown that Pb2+ exposure inhibits vesicular release and alters the distribution of presynaptic vesicles in Shaffer Collateral - CA1 synapses of rodents chronically exposed to Pb2+ during development. METHODS: In the present study, we used transmission electron microscopy to examine presynaptic vesicle pools in Mossy Fiber-CA3 synapses and in Perforant Path-Dentate Gyrus synapses of rats to determine if in vivo Pb2+ exposure altered presynaptic vesicle distribution in these hippocampal regions. Data were analyzed using T-test for each experimental endpoint. RESULTS: We found that Pb2+ exposure significantly reduced the number of vesicles in the readily releasable pool and recycling pool in Mossy Fiber-CA3 terminals. In both Mossy Fiber-CA3 terminals and in Perforant Path-Dentate Gyrus terminals, Pb2+ exposure significantly increased vesicle nearest neighbor distance in all vesicular pools (Rapidly Releasable, Recycling and Resting). We also found a reduction in the size of the postsynaptic densities of CA3 dendrites in the Pb2+ exposed group. CONCLUSIONS: In our previous work, we have demonstrated that Pb2+ exposure impairs vesicular release in Shaffer Collateral - CA1 terminals of the hippocampus and that the number of docked vesicles in the presynaptic active zone was reduced. Our current data shows that Pb2+ exposure reduces the number of vesicles that are in proximity to release sites in Mossy Fiber- CA3 terminals. Furthermore, Pb2+ exposure causes presynaptic vesicles to be further from one another, in both Mossy Fiber- CA3 terminals and in Perforant Pathway - Dentate Gyrus terminals, which may interfere with vesicle movement and release. Our findings provide a novel in vivo mechanism by which Pb2+ exposure impairs vesicle dynamics and release in the hippocampus.

Water T-maze: a useful assay for determination of repetitive behaviors in mice.

BACKGROUND: Repetitive behavior is a term used to describe a wide variety of invariant and inappropriate behaviors that occur in many diverse conditions, including autism. It is necessary to utilize and/or design rodent behavioral assays that exploit individual types of repetitive behavior so that underlying pathology and therapeutic measures can be determined. A variety of high-throughput assays to investigate lower order repetitive behaviors are available for rodents, whereas, fewer assays are available to investigate higher order repetitive behaviors, such as perseverative behavior. BTBR T(+)tf/J (BTBR) mice, harbor behavioral deficits that share similarity to the core deficits found in autism, yet have not conclusively demonstrated deficits in conventional reversal learning tasks (i.e. Morris water maze (MWM), T-maze) which are typically used to examine perseverance. NEW METHOD: By combining elements of both the MWM and T-maze, we designed a water T-maze assay to determine if perseverative behavior could become perceptible in BTBR mice. RESULTS: We found that BTBR mice show a significant impairment in reversal learning as compared to C57BL/6J (B6) mice in our water-T-maze reversal learning assay. COMPARISON OF EXISTING METHODS: Our water T-maze is sensitive, simple to perform, inexpensive and less time intensive than other tasks that can be used to measure higher order repetitive behaviors. CONCLUSIONS: Our findings suggest that our water T-maze assay is effective for determining perseverance, which is not readily revealed by using conventional methods.

Chlorination byproducts induce gender specific autistic-like behaviors in CD-1 mice.

In 2000, the Agency for Toxic Substances and Disease Registry (ATSDR) released a report concerning elevated autism prevalence and the presence water chlorination byproducts in the municipal drinking water supply in Brick Township, New Jersey. The ATSDR concluded that it was unlikely that these chemicals, specifically chloroform, bromoform (Trihalomethanes; THMs) and tetrachloroethylene (Perchloroethylene; PCE) had contributed to the prevalence of autism in this community based upon correlations between timing of exposure and/or concentration of exposure. The ATSDR conclusion may have been premature, as there is no conclusive data evidencing a correlation between a particular developmental time point that would render an individual most susceptible to toxicological insult with the development of autism. Therefore, it was our aim to determine if these chemicals could contribute to autistic like behaviors. We found that males treated with THMs and PCE have a significant reduction in the number of ultrasonic vocalizations (USVs) emitted in response to maternal separation, which are not attributed to deficits in vocal ability to or to lesser maternal care. These same males also show significantly elevated anxiety, an increase in perseverance behavior and a significant reduction in sociability. The sum of our data suggests that male, but not female mice, develop autistic like behaviors after gestational and postnatal exposure to the aforementioned chemical triad via drinking water. We believe development of such aberrant behaviors likely involves GABAergic system development.