Molecular Psychiatry最新文献

Autism spectrum disorders (ASDs) are highly heritable and result in abnormal repetitive behaviors and impairment in communication and cognitive skills. Previous studies have focused on the genetic correlation between ASDs and other neuropsychiatric disorders, but an in-depth understanding of the correlation to other disorders is required. We conducted an extensive meta-analysis of common variants identified in ASDs by genome-wide association studies (GWAS) and compared it to the consensus genes and single nucleotide polymorphisms (SNPs) of Schizophrenia (SCZ). We found approximately 75% of the GWAS genes that are associated with ASD are also associated with SCZ. We further investigated the cellular phenotypes of neurons derived from induced pluripotent stem cell (iPSC) models in ASD and SCZ. Our findings revealed that ASD and SCZ neurons initially follow divergent developmental trajectories compared to control neurons. However, despite these early diametrical differences, both ASD and SCZ neurons ultimately display similar deficits in synaptic activity as they mature. This significant genetic overlap between ASD and SCZ, coupled with the convergence towards similar synaptic deficits, highlights the intricate interplay of genetic and developmental factors in shaping the shared underlying mechanisms of these complex neurodevelopmental and neuropsychiatric disorders.

Chronic stress exerts profound negative effects on cognitive and emotional behaviours and is a major risk factor for the development of neuropsychiatric disorders. However, the molecular links between chronic stress and its deleterious effects on neuronal and synaptic function remain elusive. Here, using a combination of in vitro and in vivo approaches, we demonstrate that the upregulation of miR-186-5p triggered by chronic stress may be a key mediator of such changes, leading to synaptic dysfunction. Our results show that the expression levels of miR-186-5p are increased both in the prefrontal cortex (PFC) of mice exposed to chronic stress and in cortical neurons chronically exposed to dexamethasone. Additionally, viral overexpression of miR-186-5p in the PFC of naïve mice induces anxiety- and depressive-like behaviours. The upregulation of miR-186-5p through prolonged glucocorticoid receptor activation in vitro, or in a mouse model of chronic stress, differentially affects glutamatergic and GABAergic synaptic transmission, causing an imbalance in excitation/inhibition that leads to altered neuronal network activity. At glutamatergic synapses, we observed both a reduction in synaptic AMPARs and synaptic transmission, whereas GABAergic synaptic transmission was strengthened. These changes could be rescued in vitro by a miR-186-5p inhibitor. Overall, our results establish a novel molecular link between chronic glucocorticoid receptor activation, the upregulation of miR-186-5p and the synaptic changes induced by chronic stress, that may be amenable to therapeutic intervention.

In vivo neuroimaging research in suicide attempters has shown alterations in frontal system brain regions subserving emotional regulation, motivation, and self-perception; however, data from living individuals is limited in clarifying risk for suicide death. Postmortem neuroimaging provides an approach to study the brain in persons who died by suicide. Here, whole brain voxel-based analyses of magnetic resonance imaging gray matter volume measures were performed comparing persons confirmed by forensic investigation to have died by suicide (n = 24), versus other causes (n = 24), in a univariate model covarying for age and total brain volume; all subjects were scanned within 24 hours after death. Consistent with the hypothesis that persons who died by suicide would show lower gray matter volume in frontal system brain regions, this study of suicides showed lower gray matter volume in ventral frontal and its major connection sites including insula, striatum, and amygdala.

Ketamine, a general anesthetic, has rapid and sustained antidepressant effects when administered at lower doses. Anesthetic levels of ketamine reduce excitatory transmission by binding deep into the pore of NMDA receptors where it blocks current influx. In contrast, the molecular targets responsible for antidepressant levels of ketamine remain controversial. We used electrophysiology, structure-based mutagenesis, and molecular and kinetic modeling to investigate the effects of ketamine on NMDA receptors across an extended range of concentrations. We report functional and structural evidence that, at nanomolar concentrations, ketamine interacts with membrane-accessible hydrophobic sites on NMDA receptors, which are distinct from the established pore-blocking site. These interactions stabilize receptors in pre-open states and produce an incomplete, voltage- and pH-dependent reduction in receptor gating. Notably, this allosteric inhibitory mechanism spares brief synaptic-like receptor activations and preferentially reduces currents from receptors activated tonically by ambient levels of neurotransmitters. We propose that the hydrophobic sites we describe here account for clinical effects of ketamine not shared by other NMDA receptor open-channel blockers such as memantine and represent promising targets for developing safe and effective neuroactive therapeutics.

Obesity represents an escalating global health burden with profound medical and economic impacts. The conventional perspective on obesity revolves around its classification as a “pure” metabolic disorder, marked by an imbalance between calorie consumption and energy expenditure. Present knowledge, however, recognizes the intricate interaction of rare or frequent genetic factors that favor the development of obesity, together with the emergence of neurodevelopmental and mental abnormalities, phenotypes that are modulated by environmental factors such as lifestyle. Thirty years of human genetic research has unveiled >20 genes, causing severe early-onset monogenic obesity and ~1000 loci associated with common polygenic obesity, most of those expressed in the brain, depicting obesity as a neurological and mental condition. Therefore, obesity’s association with brain function should be better recognized. In this context, this review seeks to broaden the current perspective by elucidating the genetic determinants that contribute to both obesity and neurodevelopmental and mental dysfunctions. We conduct a detailed examination of recent genetic findings, correlating them with clinical and behavioral phenotypes associated with obesity. This includes how polygenic obesity, influenced by a myriad of genetic variants, impacts brain regions associated with addiction and reward, differentiating it from monogenic forms. The continuum between non-syndromic and syndromic monogenic obesity, with evidence from neurodevelopmental and cognitive assessments, is also addressed. Current therapeutic approaches that target these genetic mechanisms, yielding improved clinical outcomes and cognitive advantages, are discussed. To sum up, this review corroborates the genetic underpinnings of obesity, affirming its classification as a neurological disorder that may have broader implications for neurodevelopmental and mental conditions. It highlights the promising intersection of genetics, genomics, and neurobiology as a foundation for developing tailored medical approaches to treat obesity and its related neurological aspects.

While blood-based tests are readily available for various conditions, including cardiovascular diseases, type 2 diabetes, and common cancers, Alzheimer’s disease (AD) and other neurodegenerative diseases lack an early blood-based screening test that can be used in primary care. Major efforts have been made towards the investigation of approaches that may lead to minimally invasive, cost-effective, and reliable tests capable of measuring brain pathological status. Here, we review past and current technologies developed to investigate biomarkers of AD, including novel blood-based approaches and the more established cerebrospinal fluid and neuroimaging biomarkers of disease. The utility of blood as a source of AD-related biomarkers in both clinical practice and interventional trials is discussed, supported by a comprehensive list of clinical trials for AD drugs and interventions that list biomarkers as primary or secondary endpoints. We highlight that identifying individuals in early preclinical AD using blood-based biomarkers will improve clinical trials and the optimization of therapeutic treatments as they become available. Lastly, we discuss challenges that remain in the field and address new approaches being developed, such as the examination of cargo packaged within extracellular vesicles of neuronal origin isolated from peripheral blood.

Academic achievement is partly heritable and highly polygenic. However, genetic effects on academic achievement are not independent of environmental processes. We investigated whether aspects of the family environment mediated genetic effects on academic achievement across development. Our sample included 5151 children who participated in the Twins Early Development Study, as well as their parents and teachers. Data on academic achievement and family environments (parenting, home environments, and geocoded indices of neighbourhood characteristics) were available at ages 7, 9, 12 and 16. We computed educational attainment polygenic scores (PGS) and further separated genetic effects into cognitive and noncognitive PGS. Three core findings emerged. First, aspects of the family environment, but not the wider neighbourhood context, consistently mediated the PGS effects on achievement across development-accounting for up to 34.3% of the total effect. Family characteristics mattered beyond socio-economic status. Second, family environments were more robustly linked to noncognitive PGS effects on academic achievement than cognitive PGS effects. Third, when we investigated whether environmental mediation effects could also be observed when considering differences between siblings, adjusting for family fixed effects, we found that environmental mediation was nearly exclusively observed between families. This is consistent with the proposition that family environmental contexts contribute to academic development via passive gene-environment correlation processes or genetic nurture. Our results show how parents tend to shape environments that foster their children's academic development partly based on their own genetic disposition, particularly towards noncognitive skills, rather than responding to each child's genetic disposition.

Valproic acid (VPA) is an effective and widely used anti-seizure medication but is teratogenic when used during pregnancy, affecting brain and spinal cord development for reasons that remain largely unclear. Here we designed a genetic recombinase-based SOX10 reporter system in human pluripotent stem cells that enables tracking and lineage tracing of Neural Crest cells (NCCs) in a human organoid model of the developing neural tube. We found that VPA induces extensive cellular senescence and promotes mesenchymal differentiation of human NCCs. We next show that the clinically approved drug Rapamycin inhibits senescence and restores aberrant NCC differentiation trajectory after VPA exposure in human organoids and in developing zebrafish, highlighting the therapeutic promise of this approach. Finally, we identify the pioneer factor AP1 as a key element of this process. Collectively our data reveal cellular senescence as a central driver of VPA-associated neurodevelopmental teratogenicity and identifies a new pharmacological strategy for prevention. These results exemplify the power of genetically modified human stem cell-derived organoid models for drug discovery.

Treatment of Parkinson's disease (PD) is based on the use of dopaminergic drugs, such as L-Dopa and dopamine receptor agonists. These substances counteract motor symptoms, but their administration is accompanied by motor and non-motor complications. Among these latter conditions a neurobehavioral disorder similar to drug abuse, known as dopamine dysregulation syndrome (DDS), is attracting increasing interest because of its profound negative impact on the patients' quality of life. Here we replicate DDS in a PD mouse model based on a bilateral injection of 6-hydroxydopamine (6-OHDA) into the dorsal striatum. Administration of L-Dopa induced locomotor sensitization and conditioned place preference in 6-OHDA lesion, but not in control mice, indicative of the acquisition of addictive-like properties following nigrostriatal dopamine depletion. These behavioral effects were accompanied by abnormal dopamine D1 receptor (D1R) signaling in the medium spiny neurons of the dorsal striatum, leading to hyperactivation of multiple signaling cascades and increased expression of ΔFosB, a stable transcription factor involved in addictive behavior. Systemic administration of the D1R antagonist, SCH23390, abolished these effects and the development of place preference, thereby counteracting the psychostimulant-like effect of L-Dopa. The rewarding properties of L-Dopa were also prevented by chemogenetic inactivation of D1R-expressing neurons in the dorsal striatum. Our results indicate the association between abnormal D1R-mediated transmission and DDS in PD and identify potential approaches for the treatment of this disorder.

Neuroimmune interactions play a significant role in regulating synaptic plasticity in both the healthy and diseased brain. The complement pathway, an extracellular proteolytic cascade, exemplifies these interactions. Its activation triggers microglia-dependent synaptic elimination via the complement receptor 3 (CR3). Current models of pathological complement activity in the brain propose that accelerated synaptic loss resulting from overexpression of C4 (C4-OE), a gene associated with schizophrenia, follows this pathway. Here, we report that C4-mediated cortical hypoconnectivity is CR3-independent. Instead, C4-OE triggers impaired GluR1 trafficking through an intracellular mechanism involving the endosomal protein SNX27, resulting in pathological synaptic loss. Moreover, C4 circuit alterations in the prefrontal cortex, a brain region associated with neuropsychiatric disorders, were rescued by increasing neuronal levels of SNX27, which we identify as an interacting partner of this neuroimmune protein. Our results link excessive complement activity to an intracellular endo-lysosomal trafficking pathway altering synaptic plasticity.