Disposition of Proteins and Lipids in Synaptic Membrane Compartments Is Altered in Q175/Q7 Huntington's Disease Mouse Striatum.

Dysfunction at synapses is thought to be an early change contributing to cognitive, psychiatric and motor disturbances in Huntington's disease (HD). In neurons, mutant Huntingtin collects in aggregates and distributes to the same sites as wild-type Huntingtin including on membranes and in synapses. In this study, we investigated the biochemical integrity of synapses in HD mouse striatum. We performed subcellular fractionation of striatal tissue from 2 and 6-month old knock-in Q175/Q7 HD and Q7/Q7 mice. Compared to striata of Q7/Q7 mice, proteins including GLUT3, Na+/K+ ATPase, NMDAR 2b, PSD95, and VGLUT1 had altered distribution in Q175/Q7 HD striata of 6-month old mice but not 2-month old mice. These proteins are found on plasma membranes and pre- and postsynaptic membranes supporting hypotheses that functional changes at synapses contribute to cognitive and behavioral symptoms of HD. Lipidomic analysis of mouse fractions indicated that compared to those of wild-type, fractions 1 and 2 of 6 months Q175/Q7 HD had altered levels of two species of PIP2, a phospholipid involved in synaptic signaling, increased levels of cholesterol ester and decreased cardiolipin species. At 2 months, increased levels of species of acylcarnitine, phosphatidic acid and sphingomyelin were measured. EM analysis showed that the contents of fractions 1 and 2 of Q7/Q7 and Q175/Q7 HD striata had a mix of isolated synaptic vesicles, vesicle filled axon terminals singly or in clusters, and ER and endosome-like membranes. However, those of Q175/Q7 striata contained significantly fewer and larger clumps of particles compared to those of Q7/Q7. Human HD postmortem putamen showed differences from control putamen in subcellular distribution of two proteins (Calnexin and GLUT3). Our biochemical, lipidomic and EM analysis show that the presence of the HD mutation conferred age dependent disruption of localization of synaptic proteins and lipids important for synaptic function. Our data demonstrate concrete biochemical changes suggesting altered integrity of synaptic compartments in HD mice that may mirror changes in HD patients and presage cognitive and psychiatric changes that occur in premanifest HD.

The flexible use of inductive and geometric spatial categories.

The present study examined the flexibility with which people can adopt different category schemes in the spatial domain. In a location memory task, participants viewed and estimated the locations of four kinds of objects that were spatially grouped by object identity. This identity-based arrangement was either congruent or incongruent with the perceptually based, geometric categories that have been reported in previous research. Four experiments examined the conditions under which these different category schemes are used to inform estimates of locations. The results showed that use of identity information depended on the number of objects to be remembered during a trial: When one or two objects were remembered at a time, only geometric categories affected estimates, but when four objects were to be remembered, both geometric categories and identity groupings affected estimates. As memory load increases, participants rely on additional sources to inform their estimates of location.

Classification versus inference learning contrasted with real-world categories.

Categories are learned and used in a variety of ways, but the research focus has been on classification learning. Recent work contrasting classification with inference learning of categories found important later differences in category performance. However, theoretical accounts differ on whether this is due to an inherent difference between the tasks or to the implementation decisions. The inherent-difference explanation argues that inference learners focus on the internal structure of the categories--what each category is like--while classification learners focus on diagnostic information to predict category membership. In two experiments, using real-world categories and controlling for earlier methodological differences, inference learners learned more about what each category was like than did classification learners, as evidenced by higher performance on a novel classification test. These results suggest that there is an inherent difference between learning new categories by classifying an item versus inferring a feature.