Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice

Obsessive-compulsive disorder (OCD) is an anxiety-spectrum disorder characterized by persistent intrusive thoughts (obsessions) and repetitive actions (compulsions). Dysfunction of cortico-striato-thalamo-cortical circuitry is implicated in OCD, although the underlying pathogenic mechanisms are unknown. SAP90/PSD95-associated protein 3 (SAPAP3; also known as DLGAP3) is a postsynaptic scaffolding protein at excitatory synapses that is highly expressed in the striatum. Here we show that mice with genetic deletion of Sapap3 exhibit increased anxiety and compulsive grooming behaviour leading to facial hair loss and skin lesions; both behaviours are alleviated by a selective serotonin reuptake inhibitor. Electrophysiological, structural and biochemical studies of Sapap3-mutant mice reveal defects in cortico-striatal synapses. Furthermore, lentiviral-mediated selective expression of Sapap3 in the striatum rescues the synaptic and behavioural defects of Sapap3-mutant mice. These findings demonstrate a critical role for SAPAP3 at cortico-striatal synapses and emphasize the importance of cortico-striatal circuitry in OCD-like behaviours.     

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.     

The dynamic effect of macroeconomic news on the euro/US dollar exchange rate

This study investigates the impact of 70 US and EU macroeconomic news announcements on euro/dollar returns and volatility from November 2004 to April 2014. We use regime smooth transition regression to endogenously define recession and expansion. Our sample period includes the US mortgage crisis and EU sovereign debt crisis. Most news is unstable as its effect varies between these economic states. There are asymmetrical effects between recession and expansion states for both US and EU news, with most US news having a larger impact and nearly double the number of significant EU announcements. Volatility increases for over 85% of news coefficients, with more than half still being significantly different between states.     

Selection of big sagebrush by sage grouse

Feeding sites of wintering sage grouse ( Centrocercus urophasianus ) were located, one each in stands of three subspecies of big sagebrush ( Artemisia tridentata : ssp. tridentata , basin; ssp. vaseyana , mountain; and ssp. Wyomingensis , Wyoming). Evidences of differential use of plants within subspecies were observed. Whole leaves from fed-on and nonfed-on big sagebrush plants were examined for intrasubspecies chemical comparisons of crude protein, phosphorus, in vitro digestibility, and monoterpenoids. No significant differences were detected except for in vitro digestibility of Wyoming fed-on and nonfed-on big sagebrush and monoterpenoid content of basin big sagebrush. Nutritive content of all three subspecies was high, which may in part help to explain wintering sage grouse weight gains.     

In vitro digestibility of Kochia prostrata (L.) Schrad

In vitro digestibility was determined for 13 accessions of Kochia prostrata. Vegetative samples were collected in February and April. No significant differences in digestibility were detected due to month sampled or among accessions. The mean in vitro digestibility of the 13 accessions was 32.2% of dry matter digested. The accessional range was from 20.2 to 38.0% of dry matter digested.     

Wintering mule deer preference for 21 accessions of big sagebrush

Wintering mule deer showed differential browsing preference among 21 accessions of big sagebrush ( Artemisia tridentata ) grown on gardens on three different mule deer herd ranges. The Hobble Creek accession of big sagebrush was significantly preferred over the other 20 accessions across all three sites and for all three years. Accessional preference means for the study period for all sites combined ranged from 28.3 to 57.5%. The data collected support the planned release of the Hobble Creek accession as a superior cultivar of big sagebrush for use on mule deer winter ranges. Plant coumarin content was primarily under genetic control, but site factors also had an effect. Assay for coumarin compounds is useful in determining subspecies of A. tridentata but not for precise prediction of mule deer browsing preference.     

Winter nutrient content and deer use of gambel oak twigs in north central Utah

We examined winter nutritional quality of current-year bud and stem tissues from burned and unburned stands of Gambel oak ( Quercus gambelii Nutt.). Nutritional analyses were based on the amount of forage consumed by wintering mule deer. Deer use along the Utah Valley foothills averaged 6.25-10.7 cm of current-year growth. Of the tissues examined, post-fire bud tissue had the highest nutrient content, with a mean of 9.51% crude protein, 0.19% phosphorus, and 34.0% in vitro digestibility. Composite values (bud + stem) for unburned stands were slightly higher in crude protein and phosphorus and lower in digestibility than those reported in previous studies. Nutrient values from burned stands were significantly higher than those of unburned stands for all three measures. Tannin content of the burned-area regrowth was also higher. Overall forage value of Gambel oak to wintering mule deer is relatively low.     

Effects of d-amphetamine upon open field behaviour in two inbred strains of mice

Résumé Chez des souris C57BL/10J, on constate une augmentation de l'activité locomotrice durant tous les 7 jours qui suivent leur injection avec la d-amphétamine. Chez des souris BALB/cJ, cette augmentation n'apparaît pas, sauf légèrement après le quatrième jour. Des facteurs génétiques jouent un rôle important dans la détermination de la réponse comportementale à la d-amphétamine.

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This research was funded by National Institutes of Mental Health grant No. MH-18517-01. Facilities were provided by the Maryland Psychiatric Research Center, Baltimore, Maryland.     

The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum

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.