Ilse Gantois - Academia.edu (original) (raw)

Papers by Ilse Gantois

<b>Copyright information:</b>Taken from "Targeting fragile X"Genome Biology... more <b>Copyright information:</b>Taken from "Targeting fragile X"Genome Biology 2002;3(5):reviews1014.1-reviews1014.5.Published online 25 Apr 2002PMCID:PMC139362.Copyright © 2002 BioMed Central Ltd In this schematic representation, the sequence of RNA is used to illustrate the three-dimensional structure of a Gquartet; is one of a series of six random RNAs specifically bound by FMRP [4]. Four guanines form hydrogen bonds with each other in a symmetrical square planar arrangement. The G-quartet structure is stabilized by cations such as K.

Proceedings of the National Academy of Sciences, 2019

Significance Disrupting cellular mechanisms that control protein synthesis can lead to autism spe... more Significance Disrupting cellular mechanisms that control protein synthesis can lead to autism spectrum disorder (ASD) in humans. Repetitive motions, impaired social interaction, and altered vocal communication are core symptoms of ASD and can be mimicked in mice. Deletion of the protein synthesis inhibitor, eukaryotic initiation factor 4E binding protein 2 (4E-BP2), causes autistic behaviors in mice. Using a variety of conditional knockout mouse models, we found that loss of 4E-BP2 in inhibitory neurons in the brain, but not in excitatory neurons or astrocytes, causes autistic behaviors.

PloS one, 2017

Neurons in anterior cingulate cortex (aCC) project to dorsomedial striatum (DMS) as part of a cor... more Neurons in anterior cingulate cortex (aCC) project to dorsomedial striatum (DMS) as part of a corticostriatal circuit with putative roles in learning and other cognitive functions. In the present study, the spatial-cognitive importance of aCC and DMS was assessed in the hidden-platform version of the Morris water maze (MWM). Brain lesion experiments that focused on areas of connectivity between these regions indicated their involvement in spatial cognition. MWM learning curves were markedly delayed in DMS-lesioned mice in the absence of other major functional impairments, whereas there was a more subtle, but still significant influence of aCC lesions. Lesioned mice displayed impaired abilities to use spatial search strategies, increased thigmotaxic swimming, and decreased searching in the proximity of the escape platform. Additionally, aCC and DMS activity was compared in mice between the early acquisition phase (2 and 3 days of training) and the over-trained high-proficiency phase ...

Nature medicine, 2017

Fragile X syndrome (FXS) is the leading monogenic cause of autism spectrum disorders (ASD). Trinu... more Fragile X syndrome (FXS) is the leading monogenic cause of autism spectrum disorders (ASD). Trinucleotide repeat expansions in FMR1 abolish FMRP expression, leading to hyperactivation of ERK and mTOR signaling upstream of mRNA translation. Here we show that metformin, the most widely used drug for type 2 diabetes, rescues core phenotypes in Fmr1(-/y) mice and selectively normalizes ERK signaling, eIF4E phosphorylation and the expression of MMP-9. Thus, metformin is a potential FXS therapeutic.

Neurobiology of disease, Jan 12, 2015

D1-dopamine receptors (Drd1a) are highly expressed in the deep layers of the cerebral cortex and ... more D1-dopamine receptors (Drd1a) are highly expressed in the deep layers of the cerebral cortex and the striatum. A number of human diseases such as Huntington disease and schizophrenia are known to have cortical pathology involving dopamine receptor expressing neurons. To illuminate their functional role, we exploited a Cre/Lox molecular paradigm to generate Emx-1(tox) MUT mice, a transgenic line in which cortical Drd1a-expressing pyramidal neurons were selectively ablated. Emx-1(tox) MUT mice displayed prominent forelimb dystonia, hyperkinesia, ataxia on rotarod testing, heightened anxiety-like behavior, and age-dependent abnormalities in a test of social interaction. The latter occurred in the context of normal working memory on testing in the Y-maze and for novel object recognition. Some motor and behavioral abnormalities in Emx-1(tox) MUT mice overlapped with those in CamKIIα(tox) MUT transgenic mice, a line in which both striatal and cortical Drd1a-expressing cells were ablated. ...

Neurobiology of disease, 2014

Progressive cell loss is observed in the striatum, cerebral cortex, thalamus, hypothalamus, subth... more Progressive cell loss is observed in the striatum, cerebral cortex, thalamus, hypothalamus, subthalamic nucleus and hippocampus in Huntington disease. In the striatum, dopamine-responsive medium spiny neurons are preferentially lost. Clinical features include involuntary movements, gait and orofacial impairments in addition to cognitive deficits and psychosis, anxiety and mood disorders. We utilized the Cre-LoxP system to generate mutant mice with selective postnatal ablation of D1 dopamine receptor-expressing striatal neurons to determine which elements of the complex Huntington disease phenotype relate to loss of this neuronal subpopulation. Mutant mice had reduced body weight, locomotor slowing, reduced rearing, ataxia, a short stride length wide-based erratic gait, impairment in orofacial movements and displayed haloperidol-suppressible tic-like movements. The mutation was associated with an anxiolytic profile. Mutant mice had significant striatal-specific atrophy and astroglios...

Journal of Neuroscience, 2007

We generated a mouse line harboring an autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE... more We generated a mouse line harboring an autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) mutation: the ␣4 nicotinic receptor S248F knock-in strain. In this mouse, modest nicotine doses (1-2 mg/kg) elicit a novel behavior termed the dystonic arousal complex (DAC). The DAC includes stereotypical head movements, body jerking, and forelimb dystonia; these behaviors resemble some core features of ADNFLE. A marked Straub tail is an additional component of the DAC. Similar to attacks in ADNFLE, the DAC can be partially suppressed by the sodium channel blocker carbamazepine or by pre-exposure to a very low dose of nicotine (0.1 mg/kg). The DAC is centrally mediated, genetically highly penetrant, and, surprisingly, not associated with overt ictal electrical activity as assessed by (1) epidural or frontal lobe depth-electrode electroencephalography or (2) hippocampal c-fos-regulated gene expression. Heterozygous knock-in mice are partially protected from nicotine-induced seizures. The noncompetitive antagonist mecamylamine does not suppress the DAC, although it suppresses high-dose nicotine-induced wild-type-like seizures. Experiments on agonist-induced 86 Rb ϩ and neurotransmitter efflux from synaptosomes and on ␣4S248F␤2 receptors expressed in oocytes confirm that the S248F mutation confers resistance to mecamylamine blockade. Genetic background, gender, and mutant gene expression levels modulate expression of the DAC phenotype in mice. The S248F mouse thus appears to provide a model for the paroxysmal dystonic element of ADNFLE semiology. Our model complements what is seen in other ADNFLE animal models. Together, these mice cover the spectrum of behavioral and electrographic events seen in the human condition.

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2014

Cannabis use is an established risk factor for the development of schizophrenia and related psych... more Cannabis use is an established risk factor for the development of schizophrenia and related psychotic disorders. Factors that may mediate susceptibility to the psychosis-inducing effects of cannabis include the age at onset of first cannabis use, genetic predisposition, as well as interaction with other environmental risk variables. Clinical and preclinical genetic studies provide increasing evidence that, in particular, genes encoding proteins implicated in dopamine signalling are implicated in the cannabis-psychosis association. In the present review, we focus on both human and animal studies which have focused on identifying the neuronal basis of these interactions. We conclude that further studies are required to provide greater mechanistic insight into the long-term and neurodevelopmental effects of cannabis use, with implications for improved understanding of the cannabis-psychosis relationship.

Proceedings of the National Academy of Sciences, 2007

Huntington's disease is characterized by death of striatal projection neurons. We used a Cre/... more Huntington's disease is characterized by death of striatal projection neurons. We used a Cre/Lox transgenic approach to generate an animal model in which D1 dopamine receptor ( Drd1a )+ cells are progressively ablated in the postnatal brain. Striatal Drd1a, substance P , and dynorphin expression is progressively lost, whereas D2 dopamine receptor ( Drd2 ) and enkephalin expression is up-regulated. Magnetic resonance spectroscopic analysis demonstrated early elevation of the striatal choline/creatine ratio, a finding associated with extensive reactive striatal astrogliosis. Sequential MRI demonstrated a progressive reduction in striatal volume and secondary ventricular enlargement confirmed to be due to loss of striatal cells. Mutant mice had normal gait and rotarod performance but displayed hindlimb dystonia, locomotor hyperactivity, and handling-induced electrographically verified spontaneous seizures. Ethological assessment identified an increase in rearing and impairments in ...

Proceedings of the National Academy of Sciences, 2013

The multiple memory systems hypothesis posits that dorsal striatum and hippocampus are central no... more The multiple memory systems hypothesis posits that dorsal striatum and hippocampus are central nodes in independent memory systems, supporting response-based and place-based learning, respectively. Although our understanding of the function of hippocampus within this framework is relatively well established, the contribution of dorsal striatum is less clear. This in part seems to be due to the heterogeneous nature of dorsal striatum, which receives extensive topographically organized projections from higher cortical areas. Here we quantified neural activity in the intact brain while mice and humans acquired analogous versions of the Morris water maze. We found that dorsomedial striatum and medial prefrontal cortex support the initial acquisition of what is typically considered a hippocampus-dependent spatial learning task. We suggest that the circuit involving dorsomedial striatum and medial prefrontal cortex identified here plays a more task-independent role in early learning than ...

Neurobiology of Disease, 2013

Neurobeachin (NBEA), a brain-enriched multidomain scaffolding protein involved in neurotransmitte... more Neurobeachin (NBEA), a brain-enriched multidomain scaffolding protein involved in neurotransmitter release and synaptic functioning, has been identified as a candidate gene for autism spectrum disorder (ASD) in four unrelated patients haploinsufficient for NBEA. The aim of this study was to map the behavioral phenotype of Nbea +/− mice in order to understand its contribution to the pathogenesis of ASD. ASD-like behavioral variables of Nbea +/− mice were related to basal neuronal activity in different brain regions by in situ hybridizations and extracellular field recordings of synaptic plasticity in hippocampal cornu ammonis 1 (CA1) region. Levels of BDNF and phosphorylated cAMP response element-binding protein (CREB) were measured in an attempt to investigate putatively underlying changes in these neuromolecules. Nbea +/− mice exhibit several ASD-like features, including changes in self-grooming behavior, social behaviors, conditioned fear responses, and spatial learning and memory, which coincided with enhanced long-term potentiation (LTP) in their CA1 region. The observed alterations in learning and memory and hippocampal LTP are concomitant with decreased expression of the immediate early gene zif268 in dorsomedial striatum and hippocampal CA1 region, increased CREB phosphorylation, and increased hippocampal BDNF expression. These findings indicate that Nbea haploinsufficiency leads to various molecular and cellular changes that affect neuroplasticity and behavioral functions in mice, and could thus underlie the ASD symptomatology in NBEA deficient humans.

Molecular Neurobiology, 2011

Cell-cell and cell-matrix interactions are necessary for neuronal patterning and brain wiring dur... more Cell-cell and cell-matrix interactions are necessary for neuronal patterning and brain wiring during development. Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of remodelling the pericellular environment and regulating signaling pathways through cleavage of a large degradome. MMPs have been suggested to affect cerebellar development, but the specific role of different MMPs in cerebellar morphogenesis remains unclear. Here, we report a role for MMP-3 in the histogenesis of the mouse cerebellar cortex. MMP-3 expression peaks during the second week of postnatal cerebellar development and is most prominently observed in Purkinje cells (PCs). In MMP-3 deficient (MMP-3 −/−) mice, a protracted granule cell (GC) tangential migration and a delayed GC radial migration results in a thicker and persistent external granular layer, a retarded arrival of GCs in the inner granular layer, and a delayed GABAergic interneuron migration. Importantly, these neuronal migration anomalies, as well as the consequent disturbed synaptogenesis on PCs, seem to be caused by an abnormal PC dendritogenesis, which results in reduced PC dendritic trees in the adult cerebellum. Of note, these developmental and adult cerebellar defects might contribute to the aberrant motor phenotype observed in MMP-3 −/− mice and suggest an involvement of MMP-3 in mouse cerebellar development.

Journal of Pharmacological Sciences, 2013

Considerable topographic overlap exists between brain opioidergic and dopaminergic neurons. Pharm... more Considerable topographic overlap exists between brain opioidergic and dopaminergic neurons. Pharmacological blockade of the dopamine D 1 receptor (Drd1a) reverses several behavioural phenomena elicited by opioids. The present study examines the effects of morphine in adult mutant (MUT) mice expressing the attenuated diphtheria toxin-176 gene in Drd1a-expressing cells, a mutant line shown previously to undergo post-natal striatal atrophy and loss of Drd1aexpression. MUT and wild-type mice were assessed behaviourally following acute administration of 10 mg/kg morphine. Treatment with morphine reduced locomotion and rearing similarly in both genotypes but reduced total grooming only in MUT mice. Morphine-induced Straub tail and stillness were heightened in MUT mice. Chewing and sifting were decreased in MUT mice and these effects were not modified by morphine. Loss of striatal Drd1-positive cells and up-regulated D 2expression, as reflected in down-regulated D 1-like and up-regulated D 2-like binding, respectively, is not uniform along the cranio-caudal extent in this model but appears to be greater in the caudal striatum. Preferential caudal loss of μ-opioid-expression, a marker for the striosomal compartment, was seen. These data indicate that Drd1a-positive cell loss modifies the exploratory behavioural response elicited by morphine, unmasking novel morphine-induced MUT-specific behaviours and generating a hypersensitivity to morphine for others.

Journal of Muscle Research and Cell Motility, 2009

We generated a mouse line with a missense mutation (S248F) in the gene (CHRNA4) encoding the alph... more We generated a mouse line with a missense mutation (S248F) in the gene (CHRNA4) encoding the alpha4 subunit of neuronal nicotinic acetylcholine receptor (nAChR). Mutant mice demonstrate brief nicotine induced dystonia that resembles the clinical events seen in patients with the same mutation. Drug-induced dystonia is more pronounced in female mice, thus our aim was to determine if the S248F mutation changed the properties of fast- and slow-twitch muscle fibres from female mutant mice. Reverse transcriptase-PCR confirmed CHRNA4 gene expression in the brain but not skeletal muscles in normal and mutant mice. Ca(2+) and Sr(2+) force activation curves were obtained using skinned muscle fibres prepared from slow-twitch (soleus) and fast-twitch (EDL) muscles. Two significant results were found: (1) the (pCa(50) - pSr(50)) value from EDL fibres was smaller in mutant mice than in wild type (1.01 vs. 1.30), (2) the percentage force produced at pSr 5.5 was larger in mutants than in wild type (5.76 vs. 0.24%). Both results indicate a shift to slow-twitch characteristics in the mutant. This conclusion is supported by the identification of the myosin heavy chain (MHC) isoforms. Mutant EDL fibres expressed MHC I (usually only found in slow-twitch fibres) as well as MHC IIa. Despite the lack of spontaneous dystonic events, our findings suggest that mutant mice may be having subclinical events or the mutation results in a chronic alteration to muscle neural input.

Experimental Neurology, 2006

Similar to embryonic forebrain, the embryonic mesencephalon contains Fibroblast Growth Factor 2 (... more Similar to embryonic forebrain, the embryonic mesencephalon contains Fibroblast Growth Factor 2 (FGF2)-and Epidermal Growth Factor (EGF)-responsive progenitors that can be isolated as neurospheres. Developmentally, the FGF2-responsive population appears first and is thought to give rise to EGF-responsive neural stem cells. It is not known whether following this developmental switch of growth factor responsiveness ventral mesencephalic (VM)-derived neural stem cells display distinct region-specific properties. We found that murine VM-and dorsal mesencephalic (DM)-derived primary neurospheres isolated with EGF at embryonic day 14.5 differed with respect to neurosphere formation efficacy and size. VM-but not DM-derived spheres expressed En1, the molecular marker of isthmic organizer, and contained transcripts of BDNF, FGF2, IGF-I and NT-3. Both VM and DM primary neurospheres were self-renewing and gave rise to astroglial cells, but 20% of VM spheres also generated neurons. According to in vitro properties, DM-and majority of VM-derived EGF-responsive progenitors represent glial precursors. VM-but not DM-derived primary neurospheres enriched their respective conditioned medium with factors that promoted the survival of dopaminergic neurons in vitro, suggesting that ventral mesencephalic EGF-responsive progenitors are endowed with the potential to provide trophic support to nearby nascent dopaminergic neurons. These data may have implications in the treatment of Parkinson's disease.

Experimental Neurology, 2008

Parkinson's disease (PD) is characterized by loss of dopaminergic (DAergic) neurons in the substa... more Parkinson's disease (PD) is characterized by loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). It is widely believed that replacing lost SNc DA neurons is a key to longer-term effective treatment of PD motor symptoms, but generating new SNc DA neurons in PD patients has proven difficult. Following loss of tyrosine hydroxylase-positive (TH+) SNc neurons in the rodent 6-hydroxy-DA (6-OHDA) model of PD, the number of TH+ neurons partially recovers and there is evidence this occurs via phenotype "shift" from TH− to TH+ cells. Understanding how this putative phenotype shift occurs may help increase SNc DAergic neurons in PD patients. In this study we characterize the electrophysiology of SNc TH− and TH+ cells during recovery from 6-OHDA in mice. Three distinct phenotypes were observed: (1) TH− were fast discharging with a short duration action potential (AP), short afterhyperpolarization (AHP) and no small conductance Ca 2+-activated K + (SK) current; (2) TH+ were slow discharging with a long AP, long AHP and prominent SK current; and (3) cells with features "intermediate" between these TH− and TH+ phenotypes. The same 3 phenotypes were present also in the normal and D2 DA receptor knockout SNc suggesting they are more closely related to the biology of TH expression than recovery from 6-OHDA. Acute inhibition of SK channel function shifted the electrophysiological phenotype of TH+ neurons toward TH− and chronic (2 weeks) inhibition of SK channel function in normal mice shifted the neurochemical phenotype of SNc from TH+ to TH− (i.e. decreased TH+ and increased TH− cell numbers). Importantly, chronic facilitation of SK channel function shifted the neurochemical phenotype of SNc from TH− to TH+ (i.e. increased TH+ and decreased TH− cell numbers). We conclude that SK channel function bidirectionally regulates the DA phenotype of SNc cells and facilitation of SK channels may be a novel way to increase the number of SNc DAergic neurons in PD patients.

European Neuropsychopharmacology, 2008

Behavioural Brain Research, 2010

In this study we characterize the behavioural and cellular phenotype of mutant (MUT) mice with pr... more In this study we characterize the behavioural and cellular phenotype of mutant (MUT) mice with progressive loss of D1 dopamine receptor (Drd1a)-expressing cells. Adult [14-19 weeks] MUT mice showed intact working memory in the spontaneous alternation test but evidenced anxiety-like behaviour in the elevated plus maze and the light-dark test. The ethogram of mature adult MUT [average age 22 weeks] was compared with that of young adult MUT mice [average age 12 weeks]. While MUT mice evidenced hyperactivity over initial exploration at both time points, the topography of hyperactivity shifted. Moreover, initial hyperactivity was sustained over habituation at 12 weeks, but not at 22 weeks. Thus, by 22 weeks MUT mice evidenced shifts in, and mitigation of, these early phenotypic effects. However, orofacial behaviours of chewing and sifting were reduced similarly at 12 and 22 weeks. These data support the hypothesis that aspects of the mutant phenotype change with time. Quantitative autoradiography at 20 weeks revealed loss of D1-like dopamine receptor binding in the entire basal ganglia, with upregulated D2-like binding. There appear to be topographically specific interactions between normal maturational processes and compensatory mechanisms evoked subsequent to targeted ablation of D1 dopamine receptor-expressing cells. Understanding the mechanistic bases of mitigation vs persistence of individual phenotypes in relation to neural adaptation consequent to cell loss may lead to novel therapeutic strategies for basal ganglia disorders.

Behavioural Brain Research, 2010

Sex differences in humans on virtual water maze navigation are well established when overall perf... more Sex differences in humans on virtual water maze navigation are well established when overall performance is measured, e.g., by the total time taken to find the hidden platform, total path length, or quadrant dwell time during probe trials. Currently, it is unknown whether males are better spatial learners than females, or if overall performance differences reflect other aspects of the task unrelated to spatial memory. Here, males and females were tested on a virtual analogue of the Morris water maze. We devised a novel method of analysis in which each trial was divided into an initial trajectory phase and search phase. We also implemented a new measure of spatial learning during early and late training, by including trials in which subjects were only required to indicate where they thought the hidden target zone was located. Consistent with previous reports, males outperformed females on overall measures of task performance. Males also performed significantly better on all initial trajectory phase variables. Interestingly, only small (non-significant) differences were observed during the search phase and when spatial learning was tested without the constraints of a typical water maze trial. Our results suggest that spatial knowledge regarding the location of the hidden target zone is not the main factor responsible for overall sex differences in virtual water maze performance. Instead, the largest sex differences were observed during the initial trajectory phase of the trial, which is thought to depend on effective processing of distal features of the environment.

Proceedings of the National Academy of Sciences, 2019

PloS one, 2017

Nature medicine, 2017

Neurobiology of disease, Jan 12, 2015

Neurobiology of disease, 2014

Journal of Neuroscience, 2007

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2014

Proceedings of the National Academy of Sciences, 2007

Proceedings of the National Academy of Sciences, 2013

Neurobiology of Disease, 2013

Molecular Neurobiology, 2011

Journal of Pharmacological Sciences, 2013

Journal of Muscle Research and Cell Motility, 2009

Experimental Neurology, 2006

Experimental Neurology, 2008

European Neuropsychopharmacology, 2008

Behavioural Brain Research, 2010

Ten years after the identification of the gene responsible for fragile X syndrome, recent studies... more Ten years after the identification of the gene responsible for fragile X syndrome, recent studies have revealed a list of mRNAs bound by the fragile X gene product and have identified specific sequences required for the interaction between the fragile X protein and its targets. These results are a breakthrough in understanding why absence of the fragile X protein leads to mental retardation.