ABSTRACT
Tourette disorder (TD) is poorly understood, despite affecting 1/160 children. A lack of animal models possessing construct, face, and predictive validity hinders progress in the field. We used CRISPR/Cas9 genome editing to generate mice with mutations orthologous to human de novo variants in two high-confidence Tourette genes, CELSR3 and WWC1. Mice with human mutations in Celsr3 and Wwc1 exhibit cognitive and/or sensorimotor behavioral phenotypes consistent with TD. Sensorimotor gating deficits, as measured by acoustic prepulse inhibition, occur in both male and female Celsr3 TD models. Wwc1 mice show reduced prepulse inhibition only in females. Repetitive motor behaviors, common to Celsr3 mice and more pronounced in females, include vertical rearing and grooming. Sensorimotor gating deficits and rearing are attenuated by aripiprazole, a partial agonist at dopamine type II receptors. Unsupervised machine learning reveals numerous changes to spontaneous motor behavior and less predictable patterns of movement. Continuous fixed-ratio reinforcement shows that Celsr3 TD mice have enhanced motor responding and reward learning. Electrically evoked striatal dopamine release, tested in one model, is greater. Brain development is otherwise grossly normal without signs of striatal interneuron loss. Altogether, mice expressing human mutations in high-confidence TD genes exhibit face and predictive validity. Reduced prepulse inhibition and repetitive motor behaviors are core behavioral phenotypes and are responsive to aripiprazole. Enhanced reward learning and motor responding occur alongside greater evoked dopamine release. Phenotypes can also vary by sex and show stronger affection in females, an unexpected finding considering males are more frequently affected in TD.
Subject(s)
Dopamine , Mutation , Tourette Syndrome , Animals , Tourette Syndrome/genetics , Tourette Syndrome/physiopathology , Tourette Syndrome/metabolism , Mice , Female , Male , Humans , Dopamine/metabolism , Reward , Corpus Striatum/metabolism , Disease Models, Animal , Learning/physiology , Behavior, Animal , Prepulse Inhibition/genetics , Sensory Gating/geneticsABSTRACT
Protein Tyrosine Phosphatase receptor type D (PTPRD) is a member of the protein tyrosine phosphatase family that mediates cell adhesion and synaptic specification. Genetic studies have linked Ptprd to several neuropsychiatric phenotypes, including Restless Leg Syndrome (RLS), opioid abuse disorder, and antipsychotic-induced weight gain. Genome-wide association studies (GWAS) of either pediatric obsessive-compulsive traits, or Obsessive-Compulsive Disorder (OCD), have identified loci near PTPRD as genome-wide significant, or strongly suggestive for this trait. We assessed Ptprd wild-type (WT), heterozygous (HT), and knockout (KO) mice for behavioral dimensions that are altered in OCD, including anxiety and exploration (open field test, dig test), perseverative behavior (splash-induced grooming, spatial d), sensorimotor gating (prepulse inhibition), and home cage goal-directed behavior (nest building). No effect of genotype was observed in any measure of the open field test, dig test, or splash test. However, Ptprd KO mice of both sexes showed impairments in nest building behavior. Finally, female, but not male, Ptprd KO mice showed deficits in prepulse inhibition, an operational measure of sensorimotor gating that is reduced in female, but not male, OCD patients. Our results indicate that constitutive lack of Ptprd may contribute to the development of certain domains that are altered OCD, including goal-directed behavior, and reduced sensorimotor gating specifically in females.
Subject(s)
Genome-Wide Association Study , Obsessive-Compulsive Disorder , Male , Female , Animals , Mice , Goals , Obsessive-Compulsive Disorder/genetics , Genotype , Prepulse Inhibition , Mice, Knockout , Sensory Gating/genetics , Receptor-Like Protein Tyrosine Phosphatases, Class 2/geneticsABSTRACT
γ-aminobutyric acid (GABA)-ergic interneurons are essential for the physiological function of the mammalian central nervous system. Dysregulated GABAergic interneuron function has been implicated in the pathophysiology of a number of neurodevelopmental disorders including schizophrenia and autism spectrum disorder. Tangential migration is an important process to ensure the proper localization of GABAergic interneurons. Previously we found that disrupting the interaction between dopamine D1 receptor (D1R) and synaptic Ras GTPase- activating protein (SynGAP) using an interfering peptide (TAT-D1Rpep) during embryonic development impaired tangential migration. Here, we assessed the effects of prenatal disruption of D1R-SynGAP complex with the TAT-D1Rpep on the expression of several behaviours during adulthood. Mice with prenatal D1R-SynGAP disruption exhibited transiently reduced locomotor activity, abnormal sensorimotor gating, impaired sociability and deficits in visual discrimination associative learning compared to their control counterparts. Our findings reinforce the importance of GABAergic interneuron migration in the manifestation of normal motor, sensory, and cognitive behaviours of animals during adulthood.
Subject(s)
Cognition/physiology , Motor Activity/genetics , Receptors, Dopamine D1/genetics , ras GTPase-Activating Proteins/genetics , Animals , Embryonic Development/genetics , Interneurons/metabolism , Male , Mice , Receptors, Dopamine D1/metabolism , Sensory Gating/genetics , ras GTPase-Activating Proteins/metabolismABSTRACT
Neuronal calcium sensor-1 or Frequenin is a calcium sensor widely expressed in the nervous system, with roles in neurotransmission, neurite outgrowth, synaptic plasticity, learning, and motivated behaviours. Neuronal calcium sensor-1 has been implicated in neuropsychiatric disorders including autism spectrum disorder, schizophrenia, and bipolar disorder. However, the role of neuronal calcium sensor-1 in behavioural phenotypes and brain changes relevant to autism spectrum disorder have not been evaluated. We show that neuronal calcium sensor-1 deletion in the mouse leads to a mild deficit in social approach and impaired displaced object recognition without affecting social interactions, behavioural flexibility, spatial reference memory, anxiety-like behaviour, or sensorimotor gating. Morphologically, neuronal calcium sensor-1 deletion leads to increased dendritic arbour complexity in the frontal cortex. At the level of hippocampal synaptic plasticity, neuronal calcium sensor-1 deletion leads to a reduction in long-term potentiation in the dentate gyrus, but not area Cornu Ammonis 1. Metabotropic glutamate receptor-induced long-term depression was unaffected in both dentate and Cornu Ammonis 1. These studies identify roles for neuronal calcium sensor-1 in specific subregions of the brain including a phenotype relevant to neuropsychiatric disorders.
Subject(s)
Choice Behavior/physiology , Cognition/physiology , Long-Term Potentiation/genetics , Neuronal Calcium-Sensor Proteins/genetics , Neuronal Plasticity/genetics , Neuropeptides/genetics , Recognition, Psychology/physiology , Animals , Anxiety/genetics , CA1 Region, Hippocampal/physiology , Dentate Gyrus/physiopathology , Frontal Lobe/pathology , Mice , Mice, Knockout , Receptors, Metabotropic Glutamate , Sensory Gating/genetics , Social Behavior , Social Interaction , Spatial Memory/physiologyABSTRACT
Sensory processing abnormalities are consistently associated with autism, but the underlying mechanisms and treatment options are unclear. Fragile X Syndrome (FXS) is the leading known genetic cause of intellectual disabilities and autism. One debilitating symptom of FXS is hypersensitivity to sensory stimuli. Sensory hypersensitivity is seen in both humans with FXS and FXS mouse model, the Fmr1 knock out (Fmr1 KO) mouse. Abnormal sensorimotor gating may play a role in the hypersensitivity to sensory stimuli. Humans with FXS and Fmr1 KO mice show abnormalities in acoustic startle response (ASR) and prepulse inhibition (PPI) of startle, responses commonly used to quantify sensorimotor gating. Recent studies have suggested high levels of matrix metalloproteinase-9 (MMP-9) as a potential mechanism of sensory abnormalities in FXS. Here we tested the hypothesis that genetic reduction of MMP-9 in Fmr1 KO mice rescues ASR and PPI phenotypes in adult Fmr1 KO mice. We measured MMP-9 levels in the inferior colliculus (IC), an integral region of the PPI circuit, of WT and Fmr1 KO mice at P7, P12, P18, and P40. MMP-9 levels were higher in the IC of Fmr1 KO mice during early development (P7, P12), but not in adults. We compared ASR and PPI responses in young (P23-25) and adult (P50-80) Fmr1 KO mice to their age-matched wildtype (WT) controls. We found that both ASR and PPI were reduced in the young Fmr1 KO mice compared to age-matched WT mice. There was no genotype difference for ASR in the adult mice, but PPI was significantly reduced in the adult Fmr1 KO mice. The adult mouse data are similar to those observed in humans with FXS. Genetic reduction of MMP-9 in the Fmr1 KO mice resulted in a rescue of adult PPI responses to WT levels. Taken together, these results show sensorimotor gating abnormalities in Fmr1 KO mice, and suggest the potential for MMP-9 regulation as a therapeutic target to reduce sensory hypersensitivity.
Subject(s)
Fragile X Mental Retardation Protein/genetics , Matrix Metalloproteinase 9/genetics , Prepulse Inhibition/physiology , Reflex, Startle/genetics , Acoustic Stimulation/methods , Animals , Disease Models, Animal , Fragile X Mental Retardation Protein/metabolism , Fragile X Syndrome/genetics , Fragile X Syndrome/physiopathology , Genotype , Male , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Knockout , Phenotype , Prepulse Inhibition/genetics , Sensory Gating/geneticsABSTRACT
MicroRNA-124 (miR-124) is evolutionarily highly conserved among species and one of the most abundantly expressed miRNAs in the developing and mature central nervous system (CNS). Previous studies reported that miR-124 plays a role in CNS development, such as neuronal differentiation, maturation, and survival. However, the role of miR-124 in normal brain function has not yet been revealed. Here, we subjected miR-124-1+/- mice, to a comprehensive behavioral battery. We found that miR-124-1+/- mice showed impaired prepulse inhibition (PPI), methamphetamine-induced hyperactivity, and social deficits. Whole cell recordings using prefrontal cortex (PFC) slices showed enhanced synaptic transmission in layer 5 pyramidal cells in the miR-124-1+/- PFC. Based on the results of behavioral and electrophysiological analysis, we focused on genes involved in the dopaminergic system and identified a significant increase of Drd2 expression level in the miR-124-1+/- PFC. Overexpression or knockdown of Drd2 in the control or miR-124-1+/- PFC demonstrates that aberrant Drd2 signaling leads to impaired PPI. Furthermore, we identified that expression of glucocorticoid receptor gene Nr3c1, which enhances Drd2 expression, increased in the miR-124-1+/- PFC. Taken together, the current study suggests that miR-124 dosage modulates PFC function through repressing the Drd2 pathway, suggesting a critical role of miR-124 in normal PFC function.
Subject(s)
Dopamine/metabolism , Dopaminergic Neurons/metabolism , MicroRNAs/genetics , Prefrontal Cortex/physiology , 3' Untranslated Regions , Animals , Behavior, Animal , Disease Models, Animal , Gene Expression Regulation , Haploinsufficiency , Mice , Mice, Knockout , Pyramidal Cells/metabolism , RNA Interference , Sensory Gating/genetics , Synaptic Transmission/geneticsABSTRACT
The present study was aimed at evaluating whether the differences between the Roman high- (RHA) and low-avoidance (RLA) rat strains in novelty-induced behavioural inhibition/disinhibition, sensorimotor gating (i.e., prepulse inhibition, PPI) and spatial learning/memory parallel differences in the volume of brain areas related to those behavioural phenotypes. To this aim, we conducted two experiments. In Experiment 1, we evaluated the performance of adult rats from both strains, either untreated (controls) or treated with neonatal handling (NH; administered during the first 21 days of life), in a novel object exploration test (NOE), in the elevated zero-maze test (ZM) of anxiety, and in a PPI test; moreover, magnetic resonance imaging (MRI) was used to measure the volume of limbic and cortical brain regions (amygdala -Am-, hippocampus -Hc-, striatum -St-, medial prefrontal cortex -mPFc-, anterior cingulate cortex -ACC-, nucleus accumbens -NAc-) and lateral ventricles -LV-. In Experiment 2, adult rats neonatally exposed to NH and their naïve controls were submitted to the NOE and PPI tests, and to several spatial learning/memory tasks using the Morris water maze. It was found that, compared with their RLA counterparts, RHA rats show increased exploration of the novel object in the NOE test, lowered anxiety in the ZM and impaired PPI, whereas RLAs display better spatial reference learning and memory and better cognitive flexibility in a reversal task. Furthermore, MRI measurements revealed that the volume of Hc, Am and mPFc is larger in RLA vs. RHA rats, whereas the latter have dramatically enlarged lateral ventricles. NH treatment markedly enhanced exploration in the NOE test in RLA rats, improved PPI in RHA rats but impaired it in their RLA counterparts, and produced beneficial effects on spatial working memory mainly in RHA rats. Finally, exposure to NH decreased the volume of Hc and Am in the RLA strain. The results are discussed in terms of the possible relationships between strain-related volumetric brain differences and the behavioral (anxiety-related and schizophrenia-relevant) traits that distinguish RHA from RLA rats, and highlighting the finding that, in RLA rats, NH is for the first time shown to enduringly reduce the volume of Hc and Am in parallel to the decrease of anxiety and the impairment of sensorimotor gating.
Subject(s)
Brain/pathology , Hippocampus/pathology , Touch/physiology , Amygdala/physiology , Animals , Anxiety/genetics , Anxiety/physiopathology , Avoidance Learning/physiology , Behavior, Animal/physiology , Brain/physiology , Cognition/physiology , Exploratory Behavior/physiology , Hippocampus/physiology , Male , Memory, Short-Term/physiology , Prepulse Inhibition/physiology , Rats , Rats, Inbred Strains , Sensory Gating/genetics , Spatial Learning/physiologyABSTRACT
A combination of genetic and environmental risk factors has been considered as the pathogenic cause for mental disorders including schizophrenia. Here, we sought to find out whether the abnormality of the dopamine system, coupled with the exposure to modest stress, is sufficient to trigger the manifestation of schizophrenia-like behaviors. We found that exposing dopamine D4 receptor knockout (D4KO) mice with 1-week restraint stress (2 h/d) induced significant deficits in sensorimotor gating, cognitive processes, social engagement, as well as the elevated exploratory behaviors, which are reminiscent to schizophrenia phenotypes. Electrophysiological studies found that GABAergic transmission was significantly reduced in prefrontal cortical neurons from stressed D4KO mice. Additionally, administration of diazepam, a GABA enhancer, restored GABAergic synaptic responses and ameliorated some behavioral abnormalities in stressed D4KO mice. These results have revealed that the combination of 2 key genetic and environmental susceptibility factors, dopamine dysfunction and stress, is a crucial trigger for schizophrenia-like phenotypes, and GABA system in the prefrontal cortex is a downstream convergent target that mediates some behavioral outcomes.
Subject(s)
Neurons/metabolism , Prefrontal Cortex/metabolism , Receptors, Dopamine D4/genetics , Schizophrenia/genetics , Stress, Psychological/metabolism , gamma-Aminobutyric Acid/metabolism , Animals , Behavior, Animal/drug effects , Cognitive Dysfunction/genetics , Diazepam/pharmacology , Exploratory Behavior/drug effects , Female , GABA Modulators/pharmacology , Gene-Environment Interaction , Male , Mice , Mice, Knockout , Neurons/drug effects , Patch-Clamp Techniques , Prefrontal Cortex/cytology , Restraint, Physical , Schizophrenia/metabolism , Schizophrenic Psychology , Sensory Gating/drug effects , Sensory Gating/genetics , Social Behavior , Synaptic Transmission/drug effects , Synaptic Transmission/geneticsABSTRACT
Little is known about the exact genes that confer vulnerability or resilience to environmental stressors during early neurodevelopment. Partial genetic deletion of neuregulin 1 (Nrg1) moderates the neurobehavioural effects of stressors applied in adolescence and adulthood, however, no study has yet examined its impact on prenatal stress. Here we examined whether Nrg1 deficiency in mice modulated the impact of prenatal stress on various behaviours in adulthood. Male heterozygous Nrg1 mice were mated with wild-type female mice who then underwent daily restraint stress from days 13 to 19 of gestation. Surprisingly, prenatal stress had overall beneficial effects by facilitating sensorimotor gating, increasing sociability, decreasing depressive-like behaviour, and improving spatial memory in adulthood. Such benefits were not due to any increase in maternal care, as prenatal stress decreased nurturing of the offspring. Nrg1 deficiency negated the beneficial behavioural effects of prenatal stress on all measures except sociability. However, Nrg1 deficiency interacted with prenatal stress to trigger locomotor hyperactivity. Nrg1 deficiency, prenatal stress or their combination failed to alter acute stress-induced plasma corticosterone concentrations. Collectively these results demonstrate that Nrg1 deficiency moderates the effects of prenatal stress on adult behaviour, but it does so in a complex, domain-specific fashion.
Subject(s)
Behavioral Symptoms/etiology , Neuregulin-1/deficiency , Prenatal Exposure Delayed Effects/physiopathology , Stress, Psychological/physiopathology , Age Factors , Analysis of Variance , Animals , Animals, Newborn , Behavioral Symptoms/genetics , Corticosterone/blood , Dark Adaptation/genetics , Exploratory Behavior/physiology , Female , Interpersonal Relations , Male , Maternal Behavior/physiology , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neuregulin-1/genetics , Pregnancy , Recognition, Psychology/physiology , Sensory Gating/genetics , Sensory Gating/physiology , Stress, Psychological/genetics , Swimming/psychologyABSTRACT
Recently, numerous rare de novo mutations have been identified in patients diagnosed with autism spectrum disorders (ASD). However, despite the predicted loss-of-function nature of some of these de novo mutations, the affected individuals are heterozygous carriers, which would suggest that most of these candidate genes are haploinsufficient and/or lead to expression of dominant-negative forms of the protein. Here, we tested this hypothesis with the candidate ASD gene Nuak1 that we previously identified for its role in the development of cortical connectivity. We report that Nuak1 is haploinsufficient in mice with regard to its function in cortical development. Furthermore Nuak1+/- mice show a combination of abnormal behavioral traits ranging from defective spatial memory consolidation, defects in social novelty (but not social preference) and abnormal sensorimotor gating. Overall, our results demonstrate that Nuak1 haploinsufficiency leads to defects in the development of cortical connectivity and a complex array of behavorial deficits.
Subject(s)
Autism Spectrum Disorder/genetics , Cerebral Cortex/growth & development , Haploinsufficiency , Mutation , Protein Kinases/genetics , Repressor Proteins/genetics , Animals , Axons/pathology , Axons/physiology , Cerebral Cortex/pathology , Cognition/physiology , Female , Gene Expression Regulation, Developmental , Heterozygote , Humans , Male , Mice, Knockout , Protein Kinases/metabolism , Repressor Proteins/metabolism , Sensory Gating/genetics , Spatial Memory/physiologyABSTRACT
Research increasingly suggests that nitric oxide (NO) plays a role in the pathogenesis of schizophrenia. One important line of evidence comes from genetic studies, which have repeatedly detected an association between the neuronal isoform of nitric oxide synthase (nNOS or NOS1) and schizophrenia. However, the pathogenetic pathways linking nNOS, NO, and the disorder remain poorly understood. A deficit in sensorimotor gating is considered to importantly contribute to core schizophrenia symptoms such as psychotic disorganization and thought disturbance. We selected three candidate nNOS polymorphisms (Ex1f-VNTR, rs6490121 and rs41279104), associated with schizophrenia and cognition in previous studies, and tested their association with the efficiency of sensorimotor gating in healthy human adults. We found that risk variants of Ex1f-VNTR and rs6490121 (but not rs41279104) were associated with a weaker prepulse inhibition (PPI) of the acoustic startle reflex, a standard measure of sensorimotor gating. Furthermore, the effect of presence of risk variants in Ex1f-VNTR and rs6490121 was additive: PPI linearly decreased with increasing number of risk alleles, being highest in participants with no risk allele, while lowest in individuals who carry three risk alleles. Our findings indicate that NO is involved in the regulation of sensorimotor gating, and highlight one possible pathogenetic mechanism for NO playing a role in the development of schizophrenia psychosis.
Subject(s)
Nitric Oxide Synthase Type I/genetics , Polymorphism, Single Nucleotide , Sensory Gating/genetics , Adult , Exons , Female , Humans , Male , Minisatellite Repeats , Nitric Oxide/physiology , Prepulse Inhibition/genetics , Reflex, Startle/genetics , Schizophrenia/geneticsABSTRACT
We investigated the association between hypnotizability, COMT polymorphism, P50 suppression ratio, and prepulse inhibition of acoustic startle response (ASR) in 21 high (HH) and 19 low (LH) hypnotizable subjects. The frequency of Met/Met carriers of COMT polymorphysm was higher in HH than in LH group (33.3% versus 10.6%, p = .049). Increased ASR amplitude and latency and decreased prepulse inhibition at 120 ms lead interval were found in the HH compared to the LH group. The effect of COMT genotype on prepulse inhibition was observed in LH group only. No between-group differences in P50 measures were found. The obtained results suppose the participation of dopamine system in mechanisms of hypnotizability and different allocation of attentional resources in HH and LH subjects.
Subject(s)
Catechol O-Methyltransferase/genetics , Hypnosis , Sensory Gating/genetics , Adult , Catechol O-Methyltransferase/physiology , Electromyography , Electrooculography , Female , Genotype , Humans , Male , Middle Aged , Polymorphism, Genetic , Young AdultABSTRACT
Cortical sensory maps are remodeled during early life to adapt to the surrounding environment. Both sensory and contextual signals are important for induction of this plasticity, but how these signals converge to sculpt developing thalamocortical circuits remains largely unknown. Here we show that layer 1 (L1) of primary auditory cortex (A1) is a key hub where neuromodulatory and topographically organized thalamic inputs meet to tune the cortical layers below. Inhibitory interneurons in L1 send narrowly descending projections to differentially modulate thalamic drive to pyramidal and parvalbumin-expressing (PV) cells in L4, creating brief windows of intracolumnar activation. Silencing of L1 (but not VIP-expressing) cells abolishes map plasticity during the tonotopic critical period. Developmental transitions in nicotinic acetylcholine receptor (nAChR) sensitivity in these cells caused by Lynx1 protein can be overridden to extend critical-period closure. Notably, thalamocortical maps in L1 are themselves stable, and serve as a scaffold for cortical plasticity throughout life.
Subject(s)
Auditory Cortex/physiology , Interneurons/physiology , Neuronal Plasticity/physiology , Sensory Gating/physiology , Animals , Auditory Cortex/cytology , Bicuculline/pharmacology , Biguanides/pharmacology , Evoked Potentials, Auditory, Brain Stem/drug effects , Evoked Potentials, Auditory, Brain Stem/genetics , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/genetics , Female , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neuronal Plasticity/drug effects , Nicotine/pharmacology , Nicotinic Agonists/pharmacology , Otoacoustic Emissions, Spontaneous/genetics , Parvalbumins/genetics , Parvalbumins/metabolism , Sensory Gating/genetics , Serotonin Receptor Agonists/pharmacology , Vasoactive Intestinal Peptide/genetics , Vasoactive Intestinal Peptide/metabolismABSTRACT
We previously reported a 84-Kb hemi-deletion copy number variant at the SLC1A1 gene locus that reduces its expression and appeared causally linked to schizophrenia. In this report, we characterize the in vivo and in vitro consequences of reduced expression of Slc1a1 in mice. Heterozygous (HET) Slc1a1+/- mice, which more closely model the hemi-deletion we found in human subjects, were examined in a series of behavioral, anatomical and biochemical assays. Knockout (KO) mice were also included in the behavioral studies for comparative purposes. Both HET and KO mice exhibited evidence of increased anxiety-like behavior, impaired working memory, decreased exploratory activity and impaired sensorimotor gating, but no changes in overall locomotor activity. The magnitude of changes was approximately equivalent in the HET and KO mice suggesting a dominant effect of the haploinsufficiency. Behavioral changes in the HET mice were accompanied by reduced thickness of the dorsomedial prefrontal cortex. Whole transcriptome RNA-Seq analysis detected expression changes of genes and pathways involved in cytokine signaling and synaptic functions in both brain and blood. Moreover, the brains of Slc1a1+/- mice displayed elevated levels of oxidized glutathione, a trend for increased oxidative DNA damage, and significantly increased levels of cytokines. This latter finding was further supported by SLC1A1 knockdown and overexpression studies in differentiated human neuroblastoma cells, which led to decreased or increased cytokine expression, respectively. Taken together, our results suggest that partial loss of the Slc1a1 gene in mice causes haploinsufficiency associated with behavioral, histological and biochemical changes that reflect an altered redox state and may promote the expression of behavioral features and inflammatory states consistent with those observed in schizophrenia.
Subject(s)
Cognition , Excitatory Amino Acid Transporter 3/genetics , Gene Expression Regulation , Inflammation/genetics , Schizophrenia/genetics , Schizophrenic Psychology , Sensory Gating/genetics , Animals , Anxiety/genetics , Apoptosis , Behavior, Animal , Brain/metabolism , Brain/pathology , Cytokines/metabolism , DNA Damage , Disease Models, Animal , Female , Gene Regulatory Networks , Genotype , Glutathione/metabolism , Haploinsufficiency/genetics , Hippocampus/metabolism , Hippocampus/pathology , Inflammation/immunology , Inflammation/metabolism , Locomotion/genetics , Male , Mice , Mice, Knockout , Oxidation-Reduction , Oxidative Stress , Prefrontal Cortex/metabolism , Prefrontal Cortex/pathology , Schizophrenia/immunology , Schizophrenia/metabolism , Synapses/metabolismABSTRACT
Neurotransmission in dentate gyrus (DG) is critical for spatial coding, learning memory, and emotion processing. Although DG dysfunction is implicated in psychiatric disorders, including schizophrenia, underlying pathological mechanisms remain unclear. Here we report that transmembrane protein 108 (Tmem108), a novel schizophrenia susceptibility gene, is highly enriched in DG granule neurons and its expression increased at the postnatal period critical for DG development. Tmem108 is specifically expressed in the nervous system and enriched in the postsynaptic density fraction. Tmem108-deficient neurons form fewer and smaller spines, suggesting that Tmem108 is required for spine formation and maturation. In agreement, excitatory postsynaptic currents of DG granule neurons were decreased in Tmem108 mutant mice, indicating a hypofunction of glutamatergic activity. Further cell biological studies indicate that Tmem108 is necessary for surface expression of AMPA receptors. Tmem108-deficient mice display compromised sensorimotor gating and cognitive function. Together, these observations indicate that Tmem108 plays a critical role in regulating spine development and excitatory transmission in DG granule neurons. When Tmem108 is mutated, mice displayed excitatory/inhibitory imbalance and behavioral deficits relevant to schizophrenia, revealing potential pathophysiological mechanisms of schizophrenia.
Subject(s)
Cognition Disorders/genetics , Dentate Gyrus/physiology , Sensory Gating/genetics , Vesicular Transport Proteins/physiology , Animals , Animals, Newborn , Cognition Disorders/physiopathology , Dentate Gyrus/metabolism , Disease Models, Animal , Electroporation , Excitatory Postsynaptic Potentials/physiology , Fear , Genes, Reporter , Glutamic Acid/physiology , HEK293 Cells , Humans , Male , Maze Learning , Mice , Mice, Knockout , Neurons/physiology , Neurons/ultrastructure , Post-Synaptic Density/chemistry , RNA Interference , RNA, Small Interfering/genetics , Receptors, AMPA/biosynthesis , Schizophrenia/genetics , Sensory Gating/physiology , Synaptic Transmission/physiology , Vesicular Transport Proteins/deficiency , Vesicular Transport Proteins/geneticsABSTRACT
Despite the success of combination antiretroviral therapy (cART), approximately 50% of HIV-1 seropositive individuals develop HIV-1 associated neurocognitive disorders (HAND). Unfortunately, point-of-care screening tools for HAND lack sensitivity and specificity, especially in low-resource countries. Temporal processing deficits have emerged as a critical underlying dimension of neurocognitive impairments observed in HIV-1 and may provide a key target for the development of a novel point-of-care screening tool for HAND. Cross-modal prepulse inhibition (PPI; i.e., auditory, visual, or tactile prepulse stimuli) and gap-prepulse inhibition (gap-PPI; i.e., auditory, visual or tactile prepulse stimuli), two translational experimental paradigms, were used to assess the nature of temporal processing deficits in the HIV-1 transgenic (Tg) rat. Cross-modal PPI revealed a relative insensitivity to the manipulation of interstimulus interval (ISI) in HIV-1 Tg rats in comparison to controls, regardless of prestimulus modality. Gap-PPI revealed differential sensitivity to the manipulation of ISI, independent of modality, in HIV-1 Tg rats in comparison to control animals. Manipulation of context (i.e., concurrent visual or tactile stimulus) in auditory PPI revealed a differential sensitivity in HIV-1 Tg animals compared to controls. The potential utility of amodal temporal processing deficits as an innovative point-of-care screening tool was explored using a discriminant function analysis, which diagnosed the presence of the HIV-1 transgene with 97.4% accuracy. Thus, the presence of amodal temporal processing deficits in the HIV-1 Tg rat supports the hypothesis of a central temporal processing deficit in HIV-1 seropositive individuals, heralding an opportunity for the development of a point-of-care screening tool for HAND.
Subject(s)
Auditory Perception/genetics , HIV-1/genetics , Reflex, Startle/genetics , Sensory Gating/genetics , Visual Perception/genetics , Acoustic Stimulation/methods , Analysis of Variance , Animals , Female , Ovariectomy , Photic Stimulation , Rats , Rats, Inbred F344 , Rats, TransgenicABSTRACT
Developmental dyslexia is a common disorder with a strong genetic component, but the underlying molecular mechanisms are still unknown. Several candidate dyslexia-susceptibility genes, including KIAA0319, DYX1C1, and DCDC2, have been identified in humans. RNA interference experiments targeting these genes in rat embryos have shown impairments in neuronal migration, suggesting that defects in radial cortical migration could be involved in the disease mechanism of dyslexia. Here we present the first characterisation of a Kiaa0319 knockout mouse line. Animals lacking KIAA0319 protein do not show anatomical abnormalities in any of the layered structures of the brain. Neurogenesis and radial migration of cortical projection neurons are not altered, and the intrinsic electrophysiological properties of Kiaa0319-deficient neurons do not differ from those of wild-type neurons. Kiaa0319 overexpression in cortex delays radial migration, but does not affect final neuronal position. However, knockout animals show subtle differences suggesting possible alterations in anxiety-related behaviour and in sensorimotor gating. Our results do not reveal a migration disorder in the mouse model, adding to the body of evidence available for Dcdc2 and Dyx1c1 that, unlike in the rat in utero knockdown models, the dyslexia-susceptibility candidate mouse homolog genes do not play an evident role in neuronal migration. However, KIAA0319 protein expression seems to be restricted to the brain, not only in early developmental stages but also in adult mice, indicative of a role of this protein in brain function. The constitutive and conditional knockout lines reported here will be useful tools for further functional analyses of Kiaa0319.
Subject(s)
Cell Movement/genetics , Dyslexia/genetics , Dyslexia/pathology , Neocortex/pathology , Nerve Tissue Proteins/deficiency , Neurons/physiology , Age Factors , Animals , Animals, Newborn , Anxiety/etiology , Anxiety/genetics , Brain/metabolism , Dark Adaptation/genetics , Disease Models, Animal , Dyslexia/complications , Electroporation , Embryo, Mammalian , Female , Gene Expression Regulation, Developmental/genetics , Genotype , In Vitro Techniques , Ki-67 Antigen/metabolism , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Male , Membrane Potentials/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Neocortex/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurogenesis/genetics , PAX6 Transcription Factor/metabolism , Patch-Clamp Techniques , Pregnancy , Prepulse Inhibition/genetics , RNA Interference , Repressor Proteins/genetics , Repressor Proteins/metabolism , Sensory Gating/genetics , T-Box Domain Proteins/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
Reduced expression of Brain-Derived Neurotrophic Factor (BDNF) has been implicated in the pathophysiology of schizophrenia. The BDNF Val66Met polymorphism, which results in deficient activity-dependent secretion of BDNF, is associated with clinical features of schizophrenia. We investigated the effect of this polymorphism on Prepulse Inhibition (PPI), a translational model of sensorimotor gating which is disrupted in schizophrenia. We utilized humanized BDNFVal66Met (hBDNFVal66Met) mice which have been modified to carry the Val66Met polymorphism, as well as express humanized BDNF in vivo. We also studied the long-term effect of chronic corticosterone (CORT) exposure in these animals as a model of history of stress. PPI was assessed at 30ms and 100ms interstimulus intervals (ISI). Analysis of PPI at the commonly used 100ms ISI identified that, irrespective of CORT treatment, the hBDNFVal/Met genotype was associated with significantly reduced PPI. In contrast, PPI was not different between hBDNFMet/Met and hBDNFVal/Val genotype mice. At the 30ms ISI, CORT treatment selectively disrupted sensorimotor gating of hBDNFVal/Met heterozygote mice but not hBDNFVal/Val or hBDNFMet/Met mice. Analysis of startle reactivity revealed that chronic CORT reduced startle reactivity of hBDNFVal/Val male mice by 51%. However, this was independent of the effect of CORT on PPI. In summary, we provide evidence of a distinct BDNFVal66Met heterozygote-specific phenotype using the sensorimotor gating endophenotype of schizophrenia. These data have important implications for clinical studies where, if possible, the BDNFVal/Met heterozygote genotype should be distinguished from the BDNFMet/Met genotype.
Subject(s)
Brain-Derived Neurotrophic Factor/genetics , Psychotic Disorders/genetics , Reflex, Startle/genetics , Schizophrenia/genetics , Sensory Gating/genetics , Stress, Psychological/genetics , Animals , Corticosterone/pharmacology , Disease Models, Animal , Female , Male , Methionine/genetics , Mice, Inbred C57BL , Prepulse Inhibition/genetics , Steroids/pharmacology , Stress, Psychological/chemically induced , Valine/geneticsABSTRACT
Three electrophysiological endophenotypes are routinely studied in schizophrenia (SCZ): smooth pursuit eye movement (SPEM) dysfunction, deficits in P50 auditory-evoked potential inhibition, and saccadic inhibition deficits. The current study aimed to investigate the relationship between the COMT val158met polymorphism and these three endophenotypes. One hundred four SCZ patients (DSM-IV-R criteria) and 89 healthy controls were included in this study. P50 auditory-evoked potential inhibition, antisaccade paradigm and SPEM were analyzed. All individuals were genotyped for the COMT val158met. SCZ patients showed a higher rate of deficits measured by the SPEM, antisaccade and P50 inhibition paradigms without association with COMT val158met. However, in our control group, we have found an association between the Val polymorphism and the smoking status. More importantly, we have found a higher accuracy of saccades during the predictive pursuit task associated to the Met polymorphism in controls but not in SCZ patients who were receiving antidopaminergic medications. This result is in line with the hypothesis of the relationship between the Met polymorphism of the COMT gene, a higher level of dopamine in the prefrontal cortex and the role of the fronto-cerebellar loop in smooth predictive pursuit.
Subject(s)
Catechol O-Methyltransferase/genetics , Evoked Potentials, Auditory/physiology , Eye Movements/physiology , Inhibition, Psychological , Schizophrenia/genetics , Schizophrenia/physiopathology , Sensory Gating/physiology , Adult , Endophenotypes , Eye Movements/genetics , Female , Humans , Male , Middle Aged , Polymorphism, Genetic , Sensory Gating/genetics , Young AdultABSTRACT
Human genetic studies have recently suggested that the postsynaptic activity-regulated cytoskeleton-associated protein (Arc) complex is a convergence signal for several genes implicated in schizophrenia. However, the functional significance of Arc in schizophrenia-related neurobehavioral phenotypes and brain circuits is unclear. Here, we find that, consistent with schizophrenia-related phenotypes, disruption of Arc in mice produces deficits in sensorimotor gating, cognitive functions, social behaviors, and amphetamine-induced psychomotor responses. Furthermore, genetic disruption of Arc leads to concomitant hypoactive mesocortical and hyperactive mesostriatal dopamine pathways. Application of a D1 agonist to the prefrontal cortex or a D2 antagonist in the ventral striatum rescues Arc-dependent cognitive or psychomotor abnormalities, respectively. Our findings demonstrate a role for Arc in the regulation of dopaminergic neurotransmission and related behaviors. The results also provide initial biological support implicating Arc in dopaminergic and behavioral abnormalities related to schizophrenia.