Tay-Sachs and Sandhoff diseases are clinically similar neurodegenerative disorders. These two sphingolipidoses are characterized by a heritable absence of beta-hexosaminidase A resulting in defective GM2 ganglioside degradation. Through disruption of the Hexa and Hexb genes in embryonic stem cells, we have established mouse models corresponding to each disease. Unlike the two human disorders, the two mouse models show very different neurologic phenotypes. Although exhibiting biochemical and pathologic features of the disease, the Tay-Sachs model showed no neurological abnormalities. In contrast, the Sandhoff model was severely affected. The phenotypic difference between the two mouse models is the result of differences in the ganglioside degradation pathway between mice and humans.

Mice completely deficient for Dvl1, one of three mouse homologs of the Drosophila segment polarity gene Dishevelled, were created by gene targeting. Dvl1-deficient mice are viable, fertile, and structurally normal. Surprisingly, these mice exhibited reduced social interaction, including differences in whisker trimming, deficits in nest-building, less huddling contact during home cage sleeping, and subordinate responses in a social dominance test. Sensorimotor gating was abnormal, as measured by deficits in prepulse inhibition of acoustic and tactile startle. Thus, Dvl1 mutants may provide a model for aspects of several human psychiatric disorders. These results are consistent with an interpretation that common genetic mechanisms underlie abnormal social behavior and sensorimotor gating deficits and implicate Dvl1 in processes underlying complex behaviors.

Mice co-expressing the Swedish amyloid precursor protein mutation (APP Swe ) and exon 9 deletion (DE9) of the PSEN1 gene begin to develop amyloid plaques at 6-7 months of age. We demonstrate here a spatial learning deficit in 7-month-old APP Swe + PSEN1DE9 bigenic mice using an adaptation of the Barnes maze. Mice were first trained on a cued target followed by a hidden-target condition. Although bigenic mice quickly learned the cued-target version of the task, they were significantly impaired when switched to the hidden-target version. In contrast, a separate group of double-transgenic mice trained first on the spatial hidden-target version of the task were unimpaired relative to wild-type controls. We propose that processes such as general rule learning, context learning and exploratory habituation exert a greater influence when the testing environment is novel and overshadow the spatial memory deficit in naive bigenic mice. However, when cued-target training is conducted first, these processes habituate and the spatial learning deficit is unmasked. Seven-month-old APP Swe + PSEN1DE9 mice were unimpaired on tests of memory that did not involve learning the rules governing spatial associations.

We have recently disrupted Slc12a2, the gene encoding the secretory Na-K-2Cl cotransporter in mice (NKCC1) . Gramicidin perforated-patch and whole-cell recordings were performed to study GABA-induced currents in dorsal root ganglion (DRG) neurons isolated from wild-type and homozygote NKCC1 knock-out mice. In wild-type DRG neurons, strong GABA-evoked inward current was observed at the resting membrane potential, suggesting active accumulation of Cl Ϫ in these cells. This GABA-induced current was blocked by picrotoxin, a GABA A receptor blocker. The strong Cl Ϫ accumulation that gives rise to depolarizing GABA responses is caused by Na-K-2Cl cotransport because reduction of external Cl Ϫ or application of bumetanide induced a decrease in [Cl Ϫ ] i , whereas an increase in external K ϩ caused an apparent [Cl Ϫ ] i accumulation. In contrast to control neurons, little or no net current was observed at the resting membrane potential in homozygote NKCC1 mutant DRG neurons. E GABA was significantly more negative, demonstrating the absence of Cl Ϫ accumulation in these cells. Application of bumetanide induced a positive shift of E GABA , suggesting the presence of an outward Cl Ϫ transport mechanism. In agreement with an absence of GABA depolarization in DRG neurons, behavioral analysis revealed significant alterations in locomotion and pain perception in the knock-out mouse. Our results clearly demonstrate that the Na-K-2Cl cotransporter is responsible for [Cl Ϫ ] i accumulation in DRG neurons and that via regulation of intracellular Cl Ϫ , the Na-K-2Cl cotransporter participates in the modulation of GABA neurotransmission and sensory perception.

Peripheral neuropathy associated with agenesis of the corpus callosum (ACCPN) is a severe sensorimotor neuropathy associated with mental retardation, dysmorphic features and complete or partial agenesis of the corpus callosum. ACCPN is transmitted in an autosomal recessive fashion and is found at a high frequency in the province of Quebec, Canada. ACCPN has been previously mapped to chromosome 15q. The gene SLC12A6 (solute carrier family 12, member 6), which encodes the K+-Cl- transporter KCC3 and maps within the ACCPN candidate region, was screened for mutations in individuals with ACCPN. Four distinct protein-truncating mutations were found: two in the French Canadian population and two in non-French Canadian families. The functional consequence of the predominant French Canadian mutation (2436delG, Thr813fsX813) was examined by heterologous expression of wildtype and mutant KCC3 in Xenopus laevis oocytes; the truncated mutant is appropriately glycosylated and expressed at the cellular membrane, where it is non-functional. Mice generated with a targeted deletion of Slc12a6 have a locomotor deficit, peripheral neuropathy and a sensorimotor gating deficit, similar to the human disease. Our findings identify mutations in SLC12A6 as the genetic lesion underlying ACCPN and suggest a critical role for SLC12A6 in the development and maintenance of the nervous system.

Gangliosides are expressed in the outer leaflet of the plasma membrane of the cells of all vertebrates and are particularly abundant in the nervous system. Ganglioside metabolism is closely associated with the pathology of

The effects of abnormally high or low stress on learning are well established. The Barnes maze and Morris water maze are two commonly-used tests of spatial memory, of which the water maze is considered more stressful; however, until now this has not been demonstrated empirically. In the present study, mice matched for performance on commonly-used anxiety tasks were trained on either the Barnes maze or water maze or received no cognitive testing. Water-maze training induced greater increases in plasma corticosterone than did Barnes maze training, assessed 30 min. after the final session. Importantly, spatial learning was inversely correlated with corticosterone levels in the water maze but not the Barnes maze, suggesting that performance on the water maze may be more affected by test-induced stress even within wild-type subjects of the same age and gender. These findings are important when considering the appropriate cognitive tasks for any experiment in which stress responses may differ systematically across groups. KeywordsAnxiety; stress; corticosterone; Barnes maze; Morris water maze; Elevated plus maze; Light-dark activity; social dominance; behaviour The Barnes maze [3] and Morris water maze [19] are similar tasks in that they both measure the ability of a mouse to learn and remember the location of a target zone using a configuration of distal visual cues located around the testing area [11,23]. Both tasks rely on hippocampaldependent spatial reference memory and on the inherent tendencies of the subjects to escape from an aversive environment [2,27]. It has been suggested that the Barnes maze is less anxiogenic [13,21]; however, we know of no data that support this assumption.Innate anxiety and cognitive ability differ considerably among mouse strains [5,13,18] highlighting the fact that the selection of a background strain and the choice of behavioural Corresponding author: Fiona Harrison, PhD, Vanderbilt University, Division of Diabetes, Endocrinology & Metabolism, 7465 Medical Research Building IV, 2213 Garland Avenue, Nashville, TN, 37232-0475, Fiona.Harrison@Vanderbilt.edu, Phone: 615-936-1660, FAX: 615-936-1667. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The subjects were thirty 7-week-old male, C57BL/6J mice obtained from Jackson Laboratory (Bar Harbor, ME, USA; stock #000664) and left undisturbed for 1 week before testing began. Mice were housed five per cage until 1 day before testing in the Barnes or water maze, when mice were singly housed to eliminate any additional stress that may arise from test order within the cage as other mice are r...

The Barnes maze is a spatial memory task that requires subjects to learn the position of a hole that can be used to escape the brightly lit, open surface of the maze. Two experiments assessed the relative importance of spatial (extra-maze) versus proximal visible cues in solving the maze. In Experiment 1, four groups of mice were trained either with or without a discrete visible cue marking the location of the escape hole, which was either in a fixed or variable location across trials. In Experiment 2, all mice were trained with the discrete visible cue marking the target hole location. Two groups were identical to the cued-target groups from Experiment 1, with either fixed or variable escape locations. For these mice, the discrete cue either was the sole predictor of the target location or was perfectly confounded with the spatial extra-maze cues. The third group also used a cued variable target, but a curtain was drawn around the maze to prevent the use of spatial cues to guide navigation. Probe trials with all escape holes blocked were conducted to dissociate the use of spatial and discrete proximal cues. We conclude that the Barnes maze can be solved efficiently using spatial, visual cue, or serial-search strategies. However, mice showed a strong preference for using the distal room cues, even when a discrete visible cue clearly marked the escape location. Importantly, these data show that the cued-target control version of the Barnes maze as typically conducted does not dissociate spatial from nonspatial abilities.