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1.
Epilepsy Behav ; 158: 109943, 2024 Jul 12.
Article in English | MEDLINE | ID: mdl-39002280

ABSTRACT

OBJECTIVE: Functional seizures (FS) are brief, involuntary changes in behaviour or consciousness, distinct from epileptic seizures, potentially associated with psychological dissociation. Binge eating disorder (BED) was linked to psychological and somatic dissociation also. However, any connection between FS and BED is insufficiently explored. We aimed to assess BED prevalence in individuals with FS, anxiety/depression (AD), and healthy subjects (HS), to investigate dissociation's link to binge eating, and to explore psychological characteristics of FS individuals. METHOD: Participants underwent evaluations based on ILAE guidelines and DSM-5 criteria, including questionnaires assessing binge eating, dissociation, anxiety, depression and personality traits. Inclusion criteria were age > 18 years, no history of substance abuse, no history of epilepsy, and no use of medications inducing eating disorders. RESULTS: We found significantly more frequent and severe binge-eating symptoms in individuals with FS and AD compared to HS. Depression and dissociation correlated with binge-eating symptoms in both AD and FS groups. The PID-5 facet 'Perseveration' predicted binge-eating attitudes only in FS individuals; they reported more childhood emotional neglect and increased disinhibition compared do AD people. DISCUSSION: This study underscores the commonality of binge-eating symptoms in FS individuals, emphasizing its association with dissociation symptoms. This finding support the hypothesis of a link between dissociation and eating disorders. Unique clinical characteristics in individuals with FS were identified, as a compulsive dimension related to binge-eating symptoms, providing a comprehensive understanding of their psychological profile and guiding targeted therapeutic interventions.

2.
Nat Commun ; 12(1): 6715, 2021 11 18.
Article in English | MEDLINE | ID: mdl-34795271

ABSTRACT

Progress in biological imaging is intrinsically linked to advances in labeling methods. The explosion in the development of high-resolution and super-resolution imaging calls for new approaches to label targets with small probes. These should allow to faithfully report the localization of the target within the imaging resolution - typically nowadays a few nanometers - and allow access to any epitope of the target, in the native cellular and tissue environment. We report here the development of a complete labeling and imaging pipeline using genetic code expansion and non-canonical amino acids in neurons that allows to fluorescently label masked epitopes in target transmembrane proteins in live neurons, both in dissociated culture and organotypic brain slices. This allows us to image the differential localization of two AMPA receptor (AMPAR) auxiliary subunits of the transmembrane AMPAR regulatory protein family in complex with their partner with a variety of methods including widefield, confocal, and dSTORM super-resolution microscopy.


Subject(s)
Amino Acids/metabolism , Epitopes/metabolism , Membrane Proteins/metabolism , Neurons/metabolism , Staining and Labeling/methods , Animals , COS Cells , Chlorocebus aethiops , Female , HEK293 Cells , Humans , Male , Mice, Inbred C57BL , Microscopy, Confocal/methods , Optical Imaging/methods , Rats, Sprague-Dawley , Receptors, AMPA/metabolism
3.
Cell Rep ; 23(13): 3827-3838, 2018 06 26.
Article in English | MEDLINE | ID: mdl-29949767

ABSTRACT

Altered glutamatergic neurotransmission is thought to contribute to mental disorders and neurodegenerative diseases. Copy-number variation in genes associated with glutamatergic synapses represents a source of genetic variability, possibly underlying neurological and mental disease susceptibility. The GRIK4 gene encodes a high-affinity kainate receptor subunit of essentially unknown function, although de novo duplication of the 11q23.3-q24.1 locus to which it maps has been detected in autism and other disorders. To determine how changes in the dose of Grik4 affect synaptic activity, we studied mice overexpressing this gene in the forebrain. A mild gain in Grik4 enhances synaptic transmission, causing a persistent imbalance in inhibitory and excitatory activity and disturbing the circuits responsible for the main amygdala outputs. These changes in glutamatergic activity reverse when Grik4 levels are normalized; thus, they may account for the behavioral abnormalities in disorders like autism or schizophrenia.


Subject(s)
Basolateral Nuclear Complex/metabolism , Receptors, Kainic Acid/genetics , Animals , Basolateral Nuclear Complex/pathology , Behavior, Animal , Excitatory Postsynaptic Potentials/drug effects , Female , Gene Dosage , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Receptors, Glutamate/metabolism , Receptors, Kainic Acid/metabolism , Synaptic Transmission/physiology , Tetrodotoxin/pharmacology
4.
Neuroscience ; 340: 551-562, 2017 01 06.
Article in English | MEDLINE | ID: mdl-27816700

ABSTRACT

The neuropeptide PACAP modulates synaptic transmission in the hippocampus exerting multiple effects through different receptor subtypes: the underlying mechanisms have not yet been completely elucidated. The neurotransmitter acetylcholine (ACh) also exerts a well-documented modulation of hippocampal synaptic transmission and plasticity. Since PACAP was shown to stimulate ACh release in the hippocampus, we tested whether PACAP acting through ACh might indirectly modulate glutamate-mediated synaptic transmission at a pre- and/or at a post-synaptic level. Using patch clamp on rat hippocampal slices, we tested PACAP effects on stimulation-evoked AMPA receptor-mediated excitatory post-synaptic currents (EPSCsAMPA) in the CA3-CA1 synapse and on spontaneous miniature EPSCs (mEPSCs) in CA1 pyramidal neurons. A subnanomolar dose of PACAP (0.5nM) decreased EPSCsAMPA amplitude, enhanced EPSC paired-pulse facilitation (PPF) and reduced mEPSC frequency, indicating a pre-synaptic decrease of glutamate release probability: these effects were abolished by simultaneous blockade of muscarinic and nicotinic ACh receptors, indicating the involvement of endogenous ACh. The effect of subnanomolar PACAP was abolished by a PAC1 receptor antagonist but not by a VPAC receptor blocker. At a higher concentration (10nM), PACAP inhibited EPSCsAMPA: this effect persisted in the presence of ACh receptor antagonists and did not involve any change in PPF or in mEPSC frequency, thus was not mediated by ACh and was exerted post- synaptically on CA1 pyramidal neurons. We suggest that a high-affinity PAC1 receptor pre-synaptically modulates hippocampal glutamatergic transmission acting through ACh. Therefore, administration of PACAP at very low doses might be envisaged in cognitive diseases with reduced cholinergic transmission.


Subject(s)
Acetylcholine/metabolism , Glutamic Acid/metabolism , Hippocampus/metabolism , Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , Synaptic Transmission/physiology , Animals , Pituitary Adenylate Cyclase-Activating Polypeptide/administration & dosage , Presynaptic Terminals/drug effects , Presynaptic Terminals/metabolism , Pyramidal Cells/drug effects , Pyramidal Cells/metabolism , Rats, Sprague-Dawley , Rats, Wistar , Receptors, AMPA/antagonists & inhibitors , Receptors, AMPA/metabolism , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , Receptors, Vasoactive Intestinal Peptide, Type II/metabolism , Receptors, Vasoactive Intestinal Polypeptide, Type I/metabolism , Tissue Culture Techniques
5.
J Neurosci ; 35(40): 13619-28, 2015 Oct 07.
Article in English | MEDLINE | ID: mdl-26446216

ABSTRACT

The understanding of brain diseases requires the identification of the molecular, synaptic, and cellular disruptions underpinning the behavioral features that define the disease. The importance of genes related to synaptic function in brain disease has been implied in studies describing de novo germline mutations and copy number variants. Indeed, de novo copy number variations (deletion or duplication of a chromosomal region) of synaptic genes have been recently implicated as risk factors for mental retardation or autism. Among these genes is GRIK4, a gene coding for a glutamate receptor subunit of the kainate type. Here we show that mice overexpressing grik4 in the forebrain displayed social impairment, enhanced anxiety, and depressive states, accompanied by altered synaptic transmission, showing more efficient information transfer through the hippocampal trisynaptic circuit. Together, these data indicate that a single gene variation in the glutamatergic system results in behavioral symptomatology consistent with autism spectrum disorders as well as in alterations in synaptic function in regions involved in social activity. Autistic features of these mice represent powerful tools for improving diagnosis and testing of specific treatments targeting abnormalities in glutamatergic signaling related to autism spectrum disorders. SIGNIFICANCE STATEMENT: A genetic overlap exists between autism spectrum disorders (ASD), currently thought to represent a continuum of the same disorder with varying degrees of severity, and other neurodevelopmental and neuropsychiatric endophenotypes. We show that the duplication of a single gene coding for a high-affinity kainate receptor subunit (i.e., grik4) in a limited area of the brain recapitulates behavioral endophenotypes seen in humans diagnosed with autism (anhedonia, depression, anxiety, and altered social interaction), including some humans with GRIK4 duplications. Therefore, it should be possible to use mice overexpressing grik4 to directly address circuit dysfunctions associated with ASDs and test specific treatments of autism-related behaviors.


Subject(s)
Autism Spectrum Disorder/genetics , Hippocampus/cytology , Mutation/genetics , Receptors, Kainic Acid/genetics , Receptors, Kainic Acid/metabolism , Synaptic Transmission/genetics , Animals , Animals, Newborn , Autism Spectrum Disorder/physiopathology , Cell Line, Transformed , Dark Adaptation/genetics , Disease Models, Animal , Disks Large Homolog 4 Protein , Exploratory Behavior/physiology , Food Preferences , Guanylate Kinases/metabolism , HEK293 Cells , Humans , In Vitro Techniques , Interpersonal Relations , Maze Learning/physiology , Membrane Proteins/metabolism , Mice , Mice, Transgenic , Sucrose/administration & dosage , Swimming/physiology
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