DCTN1 mutation analysis in families with progressive supranuclear palsy-like phenotypes.

IMPORTANCE: Progressive supranuclear palsy (PSP) is usually sporadic, but few pedigrees with familial clustering of PSP-like phenotypes have been described. Occasionally, MAPT, C9ORF72, and TARDBP mutations have been identified. OBJECTIVE: To analyze the DCTN1 gene in 19 families with a clinical phenotype of PSP (PSP-like phenotype). DESIGN, SETTING, AND PARTICIPANTS: Sequencing of the DCTN1 gene in familial forms of PSP at a referral center among 21 patients with familial PSP-like phenotypes. In addition, 8 patients and relatives from a family carrying a DCTN1 mutation were evaluated. MAIN OUTCOMES AND MEASURES: Identification of the DCTN1 mutation and clinical description of DCTN1 mutation carriers. RESULTS: We identified a DCTN1 mutation in a large family characterized by high intrafamilial clinical phenotype variability. Two patients had PSP-like phenotypes with dystonia, vertical gaze slowness, dysexecutive syndrome, predominant axial rigidity, and midbrain atrophy on brain magnetic resonance imaging. The other patients manifested Perry syndrome, isolated parkinsonism, or a predominant behavioral variant of frontotemporal dementia. CONCLUSIONS AND RELEVANCE: Mutations of the DCTN1 gene have been previously associated with amyotrophic lateral sclerosis and with Perry syndrome, a rare autosomal dominant disorder characterized by weight loss, parkinsonism, central hypoventilation, and psychiatric disturbances. Our study demonstrates that DCTN1 mutations should be searched for in patients with clinical PSP-like phenotypes and a behavioral variant of frontotemporal dementia, especially when a familial history of dementia, psychiatric disturbances, associated parkinsonism, or an autosomal dominant disorder is present.

Early stress leads to effects on estrous cycle and differential responses to stress.

Women are more susceptible than men to stress-related mental disorders. However, few animal studies have been conducted on females. Given the interactions between gonadic hormones and the hypothalamo-pituitary-adrenal (HPA) axis, we hypothesized that the effects of early stress may be different between males and females depending on the state of their estrous cycle. Using adult Long-Evans rats of both genders, the effects of maternal deprivation were investigated on the estrous cycle length, corticosterone levels after food deprivation or restraint stress procedures, and the negative feedback efficiency of dexamethasone on the HPA axis. The individual length of the estrous cycle was evaluated using vaginal smears. Non-deprived (AFR) females mainly exhibited regular 5-day cycles (40% of the population) and 4-5-day cycles (26%), with fewer 4-day cycles (18%) and irregular cycles (16%). Comparatively, deprived (D) females displayed a significant decrease of 5-day cycles (24%) and a significant increase of irregular cycles (28%). After the restraint stress procedure, D females exhibited higher corticosterone level than AFR females during proestrous. After the food deprivation procedure, D and AFR females maintained dose-response sensitivity to the negative feedback induced by dexamethasone but only during proestrous. No differences were observed between D and AFR males under these experimental conditions. These data highlight the importance of early environmental factors in regulating the spontaneous pattern of the estrous cycle as well as gender- and stressor-dependent sensitivity of the HPA axis according to steroid levels.

Maternal deprivation induces depressive-like behaviours only in female rats.

Maternal deprivation (MD) has been developed to study the effects of early adverse experiences on behaviour and neurobiology. It has been proposed to represent a potential animal model of major depression. The purpose of our study was to examine the responses induced by MD in male and female adult Long-Evans rats in tasks designed to explore depressive-like behaviours (forced swimming test (FST), repeated open space swim test (OSST), sucrose solution consumption) and in the novel object recognition and object location tasks. A consistent sexual dimorphism was observed in the responses of male and female rats that underwent MD. In male rats, MD led to increased transitions between behaviours in the FST and increased consumption and preference for sucrose (1%) in comparison with non-deprived rats. In female rats, MD induced a decreased swimming activity on the second day of the OSST and reduced the cognitive performance in an object location task. In both sexes, MD did not alter the swimming activity in the FST and the performance in a novel object recognition task. These divergent responses in male and female rats can be related to the gender differences which exist in depression. However, due to the low amplitude of responses obtained in our study, the MD model in Long-Evans rats does not seem to mimic symptoms of major depression. In contrast, our present results suggest the use of the MD model, especially in females, as a model of the dysthymia, a mild chronic-depressive condition, which has been related to poorer maternal relationship.