The epistatic interaction between the dopamine D3 receptor and dysbindin-1 modulates higher-order cognitive functions in mice and humans

The dopamine D2 and D3 receptors are implicated in schizophrenia and its pharmacological treatments. These receptors undergo intracellular trafficking processes that are modulated by dysbindin-1 (Dys). Indeed, Dys variants alter cognitive responses to antipsychotic drugs through D2-mediated mechanisms. However, the mechanism by which Dys might selectively interfere with the D3 receptor subtype is unknown. Here, we revealed an interaction between functional genetic variants altering Dys and D3. Specifically, both in patients with schizophrenia and in genetically modified mice, concomitant reduction in D3 and Dys functionality was associated with improved executive and working memory abilities. This D3/Dys interaction produced a D2/D3 imbalance favoring increased D2 signaling in the prefrontal cortex (PFC) but not in the striatum. No epistatic effects on the clinical positive and negative syndrome scale (PANSS) scores were evident, while only marginal effects on sensorimotor gating, locomotor functions, and social behavior were observed in mice. This genetic interaction between D3 and Dys suggests the D2/D3 imbalance in the PFC as a target for patient stratification and procognitive treatments in schizophrenia

The pharmacological regulation of cellular mitophagy

Small molecules are pharmacological tools of considerable value for dissecting complex biological processes and identifying potential therapeutic interventions. Recently, the cellular quality-control process of mitophagy has attracted considerable research interest; however, the limited availability of suitable chemical probes has restricted our understanding of the molecular mechanisms involved. Current approaches to initiate mitophagy include acute dissipation of the mitochondrial membrane potential (ΔΨm) by mitochondrial uncouplers (for example, FCCP/CCCP) and the use of antimycin A and oligomycin to impair respiration. Both approaches impair mitochondrial homeostasis and therefore limit the scope for dissection of subtle, bioenergy-related regulatory phenomena. Recently, novel mitophagy activators acting independently of the respiration collapse have been reported, offering new opportunities to understand the process and potential for therapeutic exploitation. We have summarized the current status of mitophagy modulators and analyzed the available chemical tools, commenting on their advantages, limitations and current applications

Publisher Correction: Variations in Dysbindin-1 are associated with cognitive response to antipsychotic drug treatment.

In the original version of this Article, references in the Methods section incorrectly referred to references in the Supplementary References section. The relevant references (now numbered 20, 27, 42, 47, 69-80) have been removed from the Supplementary References section of the Supplementary Information file and added to the References section of the main manuscript, in both the PDF and HTML versions of the Article

Progress towards a public chemogenomic set for protein kinases and a call for contributions

Protein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of the majority of the 500+ human protein kinases remains unknown. We have developed physical and virtual collections of small molecule inhibitors, which we call chemogenomic sets, that are designed to inhibit the catalytic function of almost half the human protein kinases. In this manuscript we share our progress towards generation of a comprehensive kinase chemogenomic set (KCGS), release kinome profiling data of a large inhibitor set (Published Kinase Inhibitor Set 2 (PKIS2)), and outline a process through which the community can openly collaborate to create a KCGS that probes the full complement of human protein kinases

Dopamine transporter (DAT) genetic hypofunction in mice produces alterations consistent with ADHD but not schizophrenia or bipolar disorder

ADHD, schizophrenia and bipolar disorder are psychiatric diseases with a strong genetic component which share dopaminergic alterations. Dopamine transporter (DAT) genetics might be potentially implicated in all these disorders. However, in contrast to DAT absence, the effects of DAT hypofunction especially in developmental trajectories have been scarcely addressed. Thus, we comprehensively studied DAT hypofunctional mice (DAT+/-) from adolescence to adulthood to disentangle DAT-dependent alterations in the development of psychiatric-relevant phenotypes. From pre-adolescence onward, DAT+/- displayed a hyperactive phenotype, while responses to external stimuli and sensorimotor gating abilities were unaltered. General cognitive impairments in adolescent DAT+/- were partially ameliorated during adulthood in males but not in females. Despite this, attentional and impulsivity deficits were evident in DAT+/- adult males. At the molecular level, DAT+/- mice showed a reduced expression of Homer1a in the prefrontal cortex, while other brain regions as well as Arc and Homer1b expression were mostly unaffected. Amphetamine treatments reverted DAT+/- hyperactivity and rescued cognitive deficits. Moreover, amphetamine shifted DAT-dependent Homer1a altered expression from prefrontal cortex to striatal regions. These behavioral and molecular phenotypes indicate that a genetic-driven DAT hypofunction alters neurodevelopmental trajectories consistent with ADHD, but not with schizophrenia and bipolar disorders

Metabotropic Glutamate Receptors 5 Blockade Reverses Spatial Memory Deficits in a Mouse Model of Parkinson's Disease. : in press [full paper]

International audienc

SERS assisted sandwich immunoassay platforms for ultrasensitive and selective detection of human Thyroglobulin

: We developed an immunoassay platform for the detection of human Thyroglobulin (Tg) to be integrated with fine-needle aspiration biopsy for early detection of lymph node metastases in thyroid cancer patients. The sensing platform detects Tg by a sandwich immunoassay involving a self-assembled surface-enhanced Raman scattering (SERS) substrate assisted by functionalized gold nanoparticles that provide additional Raman signal amplification and improved molecular specificity. Specifically, the SERS-active substrates were functionalized with Tg Capture antibodies and fabricated either on-chip or on optical fiber tips by nanosphere lithography. Gold nanoparticles were functionalized with Detection antibodies and conjugated with 4-mercaptobenzoic acid, which serves as a Raman reporter. The sandwich assay platform was validated in the planar configuration and a detection limit as low as 7 pg/mL was successfully achieved. Careful morphological examination of the SERS substrates before and after Tg measurements further assessed the effective capture of nanoparticles and correlated the average nanoparticle coverage with the Tg concentration obtained by SERS measurements. The sandwich assay was successfully demonstrated on washout fluids of fine needle aspiration biopsies from cancer patients and confirmed the high specificity of the proposed methodology when complex biological matrices are considered. Finally, SERS optrodes were fabricated and successfully used to detect Tg concentration by applying the same bio-recognition strategy and Raman interrogation through an optical fiber. This opens the possibility of transferring the Tg detection approach to the optical fiber tip to develop point-of-care platforms that can be directly integrated into fine needle aspiration biopsies

Remote memories are enhanced by COMT activity through dysregulation of the endocannabinoid system in the prefrontal cortex

The prefrontal cortex (PFC) is a crucial hub for the flexible modulation of recent memories (executive functions) as well as for the stable organization of remote memories. Dopamine in the PFC is implicated in both these processes and genetic variants affecting its neurotransmission might control the unique balance between cognitive stability and flexibility present in each individual. Functional genetic variants in the catechol-O-methyltransferase (COMT) gene result in a different catabolism of dopamine in the PFC. However, despite the established role played by COMT genetic variation in executive functions, its impact on remote memory formation and recall is still poorly explored. Here we report that transgenic mice overexpressing the human COMT-Val gene (COMT-Val-tg) present exaggerated remote memories (>50 days) while having unaltered recent memories (<24 h). COMT selectively and reversibly modulated the recall of remote memories as silencing COMT Val overexpression starting from 30 days after the initial aversive conditioning normalized remote memories. COMT genetic overactivity produced a selective overdrive of the endocannabinoid system within the PFC, but not in the striatum and hippocampus, which was associated with enhanced remote memories. Indeed, acute pharmacological blockade of CB1 receptors was sufficient to rescue the altered remote memory recall in COMT-Val-tg mice and increased PFC dopamine levels. These results demonstrate that COMT genetic variations modulate the retrieval of remote memories through the dysregulation of the endocannabinoid system in the PFC