ABSTRACT
Posttraumatic stress disorder (PTSD) is a debilitating disease, which affects 8-10% of the population exposed to traumatic events. The factors that make certain individuals susceptible to PTSD and others resilient are currently unknown. Corticotropin-releasing factor receptor type 2 (CRFR2) has been implicated in mediating stress coping mechanisms. Here, we use a physiological PTSD-like animal model and an in-depth battery of tests that reflect the symptomology of PTSD to separate mice into subpopulations of "PTSD-like" and "Resilient" phenotypes. PTSD-like mice are hypervigilant, hyperalert, insomniac, have impaired attention and risk assessment, as well as accompanying attenuated corticosterone levels. Intriguingly, PTSD-like mice show long-term robust upregulation of BNST-CRFR2 mRNA levels, and BNST-CRFR2-specific lentiviral knockdown reduces susceptibility to PTSD-like behavior. Additionally, using a BNST mRNA expression array, PTSD-like mice exhibit a general transcriptional attenuation profile, which was associated with upregulation of the BNST-deacetylation enzyme, HDAC5. We suggest PTSD to be a disease of maladaptive coping.
Subject(s)
Receptors, Corticotropin-Releasing Hormone/biosynthesis , Septal Nuclei/metabolism , Stress Disorders, Post-Traumatic/metabolism , Animals , Behavior, Animal/physiology , Corticosterone/blood , Disease Models, Animal , Gene Knockdown Techniques/methods , Gene Knockdown Techniques/psychology , Histone Deacetylases/metabolism , Mice , Receptors, Corticotropin-Releasing Hormone/genetics , Resilience, Psychological , Stress Disorders, Post-Traumatic/blood , Stress Disorders, Post-Traumatic/genetics , Transcription, Genetic/physiology , Up-RegulationABSTRACT
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, increased impulsivity and emotion dysregulation. Linkage analysis followed by fine-mapping identified variation in the gene coding for Latrophilin 3 (LPHN3), a putative adhesion-G protein-coupled receptor, as a risk factor for ADHD. In order to validate the link between LPHN3 and ADHD, and to understand the function of LPHN3 in the etiology of the disease, we examined its ortholog lphn3.1 during zebrafish development. Loss of lphn3.1 function causes a reduction and misplacement of dopamine-positive neurons in the ventral diencephalon and a hyperactive/impulsive motor phenotype. The behavioral phenotype can be rescued by the ADHD treatment drugs methylphenidate and atomoxetine. Together, our results implicate decreased Lphn3 activity in eliciting ADHD-like behavior, and demonstrate its correlated contribution to the development of the brain dopaminergic circuitry.
Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Diencephalon/pathology , Diencephalon/physiopathology , Dopaminergic Neurons/pathology , Motor Activity/genetics , Nerve Degeneration/genetics , Receptors, Peptide/physiology , Animals , Atomoxetine Hydrochloride , Attention Deficit Disorder with Hyperactivity/drug therapy , Diencephalon/growth & development , Disease Models, Animal , Dopamine Uptake Inhibitors/pharmacology , Dopamine Uptake Inhibitors/therapeutic use , Dopaminergic Neurons/cytology , Dopaminergic Neurons/metabolism , Gene Knockdown Techniques/methods , Gene Knockdown Techniques/psychology , Methylphenidate/pharmacology , Methylphenidate/therapeutic use , Molecular Imaging/methods , Molecular Imaging/psychology , Motor Activity/drug effects , Motor Activity/physiology , Nerve Degeneration/pathology , Propylamines/pharmacology , Propylamines/therapeutic use , Receptors, Peptide/genetics , ZebrafishABSTRACT
The ubiquitin-proteasome system (UPS) controls the stability of most cellular proteins. The polymorphism of UPS-related genes is associated with major depression disorder, but less is known about the molecule that plays a role in depression by modulating the UPS. Melanoma antigen gene-D1 (MAGE-D1) interacts with RING E3 ubiquitin ligase and is implicated in protein degradation. MAGE-D1 may thus play an important role in the CNS via ubiquitylation. Here, we clarified a novel role of MAGE-D1 in emotional functions, namely its modulation of ubiquitylation to the serotonin transporter (SERT). The MAGE-D1 knock-out and knockdown by small interfering RNA (siRNA) in the prefrontal cortex showed depression-like behavior, such as a decrease in exploratory behavior in both the home cage and novel apparatus, a decrease in social interaction, increased immobility time during forced swimming and tail suspension, and a decrease in sucrose preference without any anxiety, or cognitive or motor dysfunction. Acute and chronic (28 d) administration of sertraline (10 mg/kg) and imipramine (20 mg/kg) reversed all or part of depression-like behavior in knock-out mice. In these mice, the serotonergic function in the prefrontal cortex and hippocampus was hypoactive, accompanied by hyperexpression of SERT attributable to a decrease in ubiquitylation. Furthermore, MAGE-D1 binds to SERT via the necdin homology domain. MAGE-D1 overexpression in cells resulted in a decrease in serotonin uptake activity and the protein level of SERT but an increase in ubiquitylated SERT. Together, the present findings suggest a novel role for MAGE-D1 in depressive behaviors: modulating SERT ubiquitylation.
Subject(s)
Antigens, Neoplasm/physiology , Depression/drug therapy , Neoplasm Proteins/physiology , Serotonin Plasma Membrane Transport Proteins/metabolism , Animals , Antidepressive Agents/pharmacology , Antigens, Neoplasm/genetics , Behavior, Animal/drug effects , Behavior, Animal/physiology , Brain/drug effects , Brain/metabolism , Brain/physiology , CHO Cells , Cricetinae , Female , Gene Knockdown Techniques/methods , Gene Knockdown Techniques/psychology , Imipramine/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microinjections , Neoplasm Proteins/genetics , Protein Binding , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/pharmacology , Serotonin/metabolism , Sertraline/pharmacology , UbiquitinationABSTRACT
Detection of specific female pheromones stimulates courtship behavior in Drosophila melanogaster males, but the chemosensory molecules, cells, and mechanisms involved remain poorly understood. Here we show that ppk25, a DEG/ENaC ion channel subunit required for normal male response to females, is expressed at highest levels in a single sexually dimorphic gustatory neuron of most taste hairs on legs and wings, but not in neurons that detect courtship-inhibiting pheromones or food. Synaptic inactivation of ppk25-expressing neurons, or knockdown of ppk25 expression in all gustatory neurons, significantly impairs male response to females, whereas gustatory expression of ppk25 rescues the courtship behavior of ppk25 mutant males. Remarkably, the only other detectable albeit significantly weaker expression of ppk25 occurs in olfactory neurons implicated in modulation of courtship behavior. However, expression of ppk25 in olfactory neurons is not required for male courtship under our experimental conditions. These data show that ppk25 functions specifically in peripheral taste neurons involved in activation of courtship behavior, an unexpected function for this type of channel. Furthermore, our work identifies a small subset of gustatory neurons with an essential role in activation of male courtship behavior, most likely in response to female pheromones.
