The Drosophila DmGluRA is required for social interaction and memory

Metabotropic glutamate receptors (mGluRs) have well-established roles in cognition and social behavior in mammals. Whether or not these roles have been conserved throughout evolution from invertebrate species is less clear. Mammals have eight mGluRs whereas Drosophila has a single DmGluRA, which has both Gi and Gq coupled signaling activity. We have utilized Drosophila to examine the role of DmGluRA in social behavior and various phases of memory. We have found that flies that are homozygous or heterozygous for loss of function mutations of DmGluRA have impaired social behavior in male Drosophila. Futhermore, flies that are heterozygous for loss of function mutations of DmGluRA have impaired learning during training, immediate-recall memory, short-term memory, and long-term memory as young adults. This work demonstrates a role for mGluR activity in both social behavior and memory in Drosophila

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS

Affective lability and difficulties with regulation are differentially associated with amygdala and prefrontal response in women with Borderline Personality Disorder

The present neuroimaging study investigated two aspects of difficulties with emotion associated with Borderline Personality Disorder (BPD()): affective lability and difficulty regulating emotion. While these two characteristics have been previously linked to BPD symptomology, it remains unknown whether individual differences in affective lability and emotion regulation difficulties are subserved by distinct neural substrates within a BPD sample. To address this issue, sixty women diagnosed with BPD were scanned while completing a task that assessed baseline emotional reactivity as well as top-down emotion regulation. More affective instability, as measured by the Affective Lability Scale (ALS()), positively correlated with greater amygdala responses on trials assessing emotional reactivity. Greater difficulties with regulating emotion, as measured by the Difficulties with Emotion Regulation Scale (DERS()), was negatively correlated with left inferior frontal gyrus (IFG()) recruitment on trials assessing regulatory ability. These findings suggest that, within a sample of individuals with BPD, greater bottom-up amygdala activity is associated with heightened affective lability. By contrast, difficulties with emotion regulation are related to reduced IFG recruitment during emotion regulation. These results point to distinct neural mechanisms for different aspects of BPD symptomology

Affective lability and difficulties with regulation are differentially associated with amygdala and prefrontal response in women with Borderline Personality Disorder

The present neuroimaging study investigated two aspects of difficulties with emotion associated with Borderline Personality Disorder (BPD): affective lability and difficulty regulating emotion. While these two characteristics have been previously linked to BPD symptomology, it remains unknown whether individual differences in affective lability and emotion regulation difficulties are subserved by distinct neural substrates within a BPD sample. To address this issue, sixty women diagnosed with BPD were scanned while completing a task that assessed baseline emotional reactivity as well as top-down emotion regulation. More affective instability, as measured by the Affective Lability Scale (ALS), positively correlated with greater amygdala responses on trials assessing emotional reactivity. Greater difficulties with regulating emotion, as measured by the Difficulties with Emotion Regulation Scale (DERS), was negatively correlated with left Inferior Frontal Gyrus (IFG) recruitment on trials assessing regulatory ability. These findings suggest that, within a sample of individuals with BPD, greater bottom-up amygdala activity is associated with heightened affective lability. By contrast, difficulties with emotion regulation are related to reduced IFG recruitment during emotion regulation. These results point to distinct neural mechanisms for different aspects of BPD symptomology

PDE-4 Inhibition Rescues Aberrant Synaptic Plasticity in Drosophila and Mouse Models of Fragile X Syndrome

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS

Development of the alopecia areata scale for clinical use: Results of an academic–industry collaborative effort

The current classification for alopecia areata (AA) does not provide a consistent assessment of disease severity. To develop an AA severity scale based on expert experience. A modified Delphi process was utilized. An advisory group of 22 AA clinical experts from the United States was formed to develop this AA scale. Representatives from the pharmaceutical industry provided feedback during its development. Survey responses were used to draft severity criteria, aspiring to develop a simple scale that may be easily applied in clinical practice. A consensus vote was held to determine the final AA severity statement, with all AA experts agreeing to adopt the proposed scale. The scale is a static assessment intended to be used in clinical practice and not clinical trials. The final AA disease severity scale, anchored in the extent of hair loss, captures key features commonly used by AA experts in clinical practice. This scale will better aid clinicians in appropriately assessing severity in patients with this common disease