ABSTRACT
Activation of microglial cells accompanies the progression of many neurodegenerative disorders, including Alzheimer's disease (AD). Development of molecular imaging tools specific to microglia can help elucidate the mechanism through which microglia contribute to the pathogenesis and progression of neurodegenerative disorders. Through analysis of published genetic, transcriptomic, and proteomic data sets, we identified 19 genes with microglia-specific expression that we then ranked based on association with the AD characteristics, change in expression, and potential druggability of the target. We believe that the process we used to identify and rank microglia-specific genes is broadly applicable to the identification and evaluation of targets in other disease areas and for applications beyond molecular imaging.
Subject(s)
Alzheimer Disease , Neurodegenerative Diseases , Humans , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Microglia/metabolism , Proteomics , Neurodegenerative Diseases/metabolism , Neuroimaging , Positron-Emission Tomography/methodsABSTRACT
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with an estimated heritability of around 70%. Although the largest genome-wide association study (GWAS) meta-analysis on ADHD identified independent loci conferring risk to the disorder, the molecular mechanisms underlying the genetic basis of the disorder remain to be elucidated. To explore ADHD biology, we ran a two-step transcriptome profiling in peripheral blood mononuclear cells (PBMCs) of 143 ADHD subjects and 169 healthy controls. Through this exploratory study we found eight differentially expressed genes in ADHD. These results highlight promising candidate genes and gene pathways for ADHD and support the use of peripheral tissues to assess gene expression signatures for ADHD.
Subject(s)
Attention Deficit Disorder with Hyperactivity/diagnosis , Attention Deficit Disorder with Hyperactivity/genetics , Gene Expression Profiling/methods , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study/methods , Adult , Case-Control Studies , Female , Humans , Male , Middle Aged , Young AdultABSTRACT
Cortical interneurons (CINs) originate in the ganglionic eminences (GEs) and migrate tangentially to the cortex guided by different attractive and repulsive cues. Once inside the cortex, the cellular and molecular mechanisms determining the migration of CINs along the rostrocaudal axis are less well understood. Here, we investigated the cortical distribution of CINs originating in the medial and caudal GEs at different time points. Using molecular and genetic labeling, we showed that, in the mouse, early- and late-born CINs (E12 versus E15) are differentially distributed along the rostrocaudal axis. Specifically, late-born CINs are preferentially enriched in cortical areas closer to their respective sites of origin in the medial or caudal GE. Surprisingly, our in vitro experiments failed to show a preferential migration pattern along the rostrocaudal axis for medial- or caudal-born CINs. Moreover, in utero transplantation experiments suggested that the rostrocaudal dispersion of CINs depends on the developmental stage of the host brain and is limited by the migration time and the increasing size of the developing brain. These data suggest that the embryonic expansion of the cortex contributes to the rostrocaudal distribution of CINs.
Subject(s)
Brain/growth & development , Cerebral Cortex/cytology , GABAergic Neurons/cytology , Animals , Brain/embryology , Brain/physiology , Cell Lineage , Cell Movement , Cerebral Cortex/embryology , Cerebral Cortex/metabolism , Embryo, Mammalian/cytology , Embryo, Mammalian/metabolism , GABAergic Neurons/metabolism , Mice , Mice, Knockout , Organ Size , Somatosensory Cortex/cytology , Somatosensory Cortex/embryology , Somatosensory Cortex/metabolism , Thyroid Nuclear Factor 1/deficiency , Thyroid Nuclear Factor 1/genetics , Thyroid Nuclear Factor 1/metabolism , gamma-Aminobutyric Acid/metabolismABSTRACT
Adhesion G protein-coupled receptor L3 (ADGRL3, LPHN3) has putative roles in neuronal migration and synapse function. Various polymorphisms in ADGRL3 have been linked with an increased risk of attention deficit/hyperactivity disorder (ADHD). In this study, we examined the characteristics of Adgrl3-deficient mice in multiple behavioural domains related to ADHD: locomotive activity, impulsivity, gait, visuospatial and recognition memory, sociability, anxiety-like behaviour and aggression. Additionally, we investigated the effect of Adgrl3-depletion at the transcriptomic level by RNA-sequencing three ADHD-relevant brain regions: prefrontal cortex (PFC), hippocampus and striatum. Adgrl3-/- mice show increased locomotive activity across all tests and subtle gait abnormalities. These mice also show impairments across spatial memory and learning domains, alongside increased levels of impulsivity and sociability with decreased aggression. However, these alterations were absent in Adgrl3+/- mice. Across all brain regions tested, the numbers of genes found to exhibit differential expression was relatively small, indicating a specific pathway of action, rather than a broad neurobiological perturbation. Gene-set analysis of differential expression in the PFC detected a number of ADHD-relevant pathways including dopaminergic synapses as well as cocaine and amphetamine addiction. The Slc6a3 gene coding for the dopamine transporter was the most dysregulated gene in the PFC. Unexpectedly, several neurohormone/peptides which are typically only expressed in the hypothamalus were found to be dysregulated in the striatum. Our study further validates Adgrl3 constitutive knockout mice as an experimental model of ADHD while providing neuroanatomical targets for future studies involving ADGRL3 modified models. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.
Subject(s)
Aggression/physiology , Attention Deficit Disorder with Hyperactivity/genetics , Impulsive Behavior/physiology , Receptors, G-Protein-Coupled/physiology , Receptors, Peptide/physiology , Animals , Behavior, Animal/physiology , Brain/metabolism , Disease Models, Animal , Dopamine Plasma Membrane Transport Proteins/metabolism , Female , Gene Expression , Male , Mice, Inbred C57BL , Mice, Knockout , Receptors, G-Protein-Coupled/genetics , Receptors, Peptide/geneticsABSTRACT
Animal and cellular models are essential tools for all areas of biological research including neuroscience. Model systems can also be used to investigate the pathophysiology of psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In this review, we provide a summary of animal and cellular models for three genes linked to ADHD and ASD in human patients - CNTNAP2, ADGRL3, and PARK2. We also highlight the strengths and weaknesses of each model system. By bringing together behavioral and neurobiological data, we demonstrate how a cross-species approach can provide integrated insights into gene function and the pathogenesis of ADHD and ASD. The knowledge gained from transgenic models will be essential to discover and validate new treatment targets for these disorders.
Subject(s)
Attention Deficit Disorder with Hyperactivity/physiopathology , Autism Spectrum Disorder/physiopathology , Animals , Disease Models, Animal , Drosophila , Humans , Membrane Proteins/metabolism , Mice , Models, Biological , Nerve Tissue Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , Ubiquitin-Protein Ligases/metabolism , ZebrafishABSTRACT
The postnatal functions of the Dlx1&2 transcription factors in cortical interneurons (CINs) are unknown. Here, using conditional Dlx1, Dlx2, and Dlx1&2 knockouts (CKOs), we defined their roles in specific CINs. The CKOs had dendritic, synaptic, and survival defects, affecting even PV+ CINs. We provide evidence that DLX2 directly drives Gad1, Gad2, and Vgat expression, and show that mutants had reduced mIPSC amplitude. In addition, the mutants formed fewer GABAergic synapses on excitatory neurons and had reduced mIPSC frequency. Furthermore, Dlx1/2 CKO had hypoplastic dendrites, fewer excitatory synapses, and reduced excitatory input. We provide evidence that some of these phenotypes were due to reduced expression of GRIN2B (a subunit of the NMDA receptor), a high confidence Autism gene. Thus, Dlx1&2 coordinate key components of CIN postnatal development by promoting their excitability, inhibitory output, and survival.
Subject(s)
Cerebral Cortex/growth & development , GABAergic Neurons/physiology , Homeodomain Proteins/physiology , Interneurons/physiology , Synapses/physiology , Transcription Factors/physiology , gamma-Aminobutyric Acid/biosynthesis , Animals , Cerebral Cortex/cytology , Female , GABAergic Neurons/cytology , Gene Expression Regulation, Developmental , Glutamate Decarboxylase/metabolism , Homeodomain Proteins/genetics , Interneurons/cytology , Male , Mice, Knockout , Miniature Postsynaptic Potentials , Transcription Factors/genetics , Vesicular Inhibitory Amino Acid Transport Proteins/metabolismABSTRACT
Bacterial intoxication associated with inflammatory conditions during development can impair brain functions, in particular evolutionarily novel forms of memory, such as explicit learning. Little is known about the dangers of early-life inflammation on more basic forms of learning, for example, the acquisition of motor escape abilities, which are generally better preserved under pathological conditions. To address this limitation in knowledge, an inflammatory response was elicited in Wistar pups by lipopolysaccharide (LPS) injections (25 µg/kg) on postnatal days P15, P18 and P21. The acquisition of escape behaviour was tested from P77 by active avoidance footshock model and water maze. Open-field behaviour and blood corticosterone levels were also measured. Rat brain tissue was collected from pups 2 h post-injection and from adult rats which either underwent escape training on P77-P81 or remained untrained. mRNA levels of developmental brain plasticity factors MMP-9 and TIMP-1 were investigated in the medial prefrontal cortex and ventral/dorsal hippocampus. LPS-challenged rats displayed moderately deficient escape responses in both memory tests, increased freezing behaviour and, surprisingly, reduced blood cortisol levels. Mmp9 and Timp1, and their ratio to one another, were differentially altered in pups versus adult untrained rats but remained unchanged overall in rats trained in either learning task. Together, our data indicate that systemic pro-inflammatory response during early postnatal development has long-lasting effects, including on the acquisition of motor escape abilities and plasticity factor expression, into adulthood. Our data suggest that altered stress response could possibly mediate these deviations and repeated training might generate positive effects on plasticity under the employed conditions.
Subject(s)
Avoidance Learning/drug effects , Brain/metabolism , Escape Reaction/drug effects , Gene Expression Regulation, Developmental/drug effects , Lipopolysaccharides/toxicity , Matrix Metalloproteinase 9/metabolism , Tissue Inhibitor of Metalloproteinase-1/metabolism , Age Factors , Animals , Animals, Newborn , Avoidance Learning/physiology , Brain/drug effects , Corticosterone/blood , Escape Reaction/physiology , Exploratory Behavior/drug effects , Female , Male , Matrix Metalloproteinase 9/genetics , Maze Learning/drug effects , RNA, Messenger/metabolism , Rats , Rats, Wistar , Statistics, Nonparametric , Time Factors , Tissue Inhibitor of Metalloproteinase-1/geneticsABSTRACT
Methyl-CpG binding protein 2 (MECP2) is a chromosome-binding protein that regulates the development and maintenance of brain circuits. Altered function of the protein product of MECP2 plays an important role in the etiology of many neurodevelopmental disorders. Mutations involving a loss of function are implicated in the etiology of Rett syndrome, intellectual disability, psychosis and severe encephalopathy. Conversely, MECP2 duplications have been identified in autism and intellectual disability. MECP2 action is dependent on neuronal function, as the DNA binding is modulated by activity, and it is phosphorylated in response to stimulation. Although MECP2 is considered a major risk factor for neurodevelopmental disorders, and it is a mediator of activity-dependent mechanisms, the expression levels in response to neuronal activity have never been measured. We studied the expression of Mecp2 protein and RNA in mice neuronal cultures in response to different stimulation conditions and in the presence of insulin-like growth factor1 (IGF1): a growth factor involved in brain development and plasticity. The stimulation protocols were selected according to their ability to induce different forms of synaptic plasticity: rapid depolarization, feed-forward plasticity (LTP, LTD) and feedback forms of plasticity (TTX, KCl). We find a significant reduction of Mecp2 protein nuclear expression in neurons in response to stimuli that induce a potentiation of neuronal response, suggesting that Mecp2 protein expression is modulated by neuronal activation. Application of IGF1 to the cultures induces an increase in the expression of Mecp2 transcript and nuclear Mecp2 protein in neurons. These results show that Mecp2 is responsive to neuronal stimulation and IGF1, and different stimuli have different effects on Mecp2 expression; this differential response may have downstream effects on functional mechanisms regulating brain development and plasticity.
Subject(s)
Insulin-Like Growth Factor I/pharmacology , Methyl-CpG-Binding Protein 2/metabolism , Neurons/physiology , Animals , Animals, Newborn , Cells, Cultured , Cerebral Cortex/cytology , Methyl-CpG-Binding Protein 2/genetics , Mice , Neuronal Plasticity , Neurons/drug effects , RNA/metabolismABSTRACT
Rett Syndrome (RTT) is a severe neurodevelopmental disorder characterized by an apparently normal development followed by an arrest and subsequent regression of cognitive and psychomotor abilities. At present, RTT has no definitive cure and the treatment of RTT represents a largely unmet clinical need. Following partial elucidation of the underlying neurobiology of RTT, a new treatment has been proposed, Mecasermin (recombinant human Insulin-Like Growth Factor 1), which, in addition to impressive evidence from preclinical murine models of RTT, has demonstrated safety in human studies of patients with RTT. The present clinical study examines the disease severity as assessed by clinicians (International Scoring System: ISS), social and cognitive ability assessed by two blinded, independent observers (RSS: Rett Severity Score), and changes in brain activity (EEG) parameters of ten patients with classic RTT and ten untreated patients matched for age and clinical severity. Significant improvement in both the ISS (p = 0.0106) and RSS (p = 0.0274) was found in patients treated with IGF1 in comparison to untreated patients. Analysis of the novel RSS also suggests that patients treated with IGF1 have a greater endurance to social and cognitive testing. The present clinical study adds significant preliminary evidence for the use of IGF-1 in the treatment of RTT and other disorders of the autism spectrum.