title: Altered fronto-striatal functions in the Gdi1-null mouse model of X-linked Intellectual Disability.
abstract: RAB-GDP dissociation inhibitor 1 (GDI1) loss-of-function mutations are responsible for a form of non-specific X-linked Intellectual Disability (XLID) where the only clinical feature is cognitive impairment. GDI1 patients are impaired in specific aspects of executive functions and conditioned response, which are controlled by fronto-striatal circuitries. Previous molecular and behavioral characterization of the Gdi1-null mouse revealed alterations in the total number/distribution of hippocampal and cortical synaptic vesicles as well as hippocampal short-term synaptic plasticity, and memory deficits. In this study, we employed cognitive protocols with high translational validity to human condition that target the functionality of cortico-striatal circuitry such as attention and stimulus selection ability with progressive degree of complexity. We previously showed that Gdi1-null mice are impaired in some hippocampus-dependent forms of associative learning assessed by aversive procedures. Here, using appetitive-conditioning procedures we further investigated associative learning deficits sustained by the fronto-striatal system. We report that Gdi1-null mice are impaired in attention and associative learning processes, which are a key part of the cognitive impairment observed in XLID patients.
authors.affiliation: Molecular Genetics of Intellectual Disability Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Morè
authors.affiliation: pRED, Pharma Research & Early Development, NORD Neuroscience, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Switzerland.
authors.forename: Basil
authors.initials: B
authors.lastname: Künnecke
authors.affiliation: Neuroimmunology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Latefa
authors.initials: L
authors.lastname: Yekhlef
authors.affiliation: pRED, Pharma Research & Early Development, NORD Neuroscience, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bruns
authors.affiliation: Department of Pharmacy, Section of Pharmacology and Toxicology, Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Marte
authors.affiliation: Department of Pharmacy, Section of Pharmacology and Toxicology, Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Fedele
authors.affiliation: Molecular Genetics of Intellectual Disability Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Bianchi
authors.affiliation: Neuroimmunology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Taverna
authors.affiliation: pRED, Pharma Research & Early Development, NORD Neuroscience, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gatti
authors.affiliation: Molecular Genetics of Intellectual Disability Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: dadamo.patrizia@hsr.it.
authors.forename: Patrizia
authors.initials: P
authors.lastname: D'Adamo
mesh_terms: D000679:Amygdala / Q000000981:diagnostic imaging / Q000503:physiopathology; D000818:Animals; D001245:Association Learning / Q000502:physiology; D001288:Attention / Q000502:physiology; D003213:Conditioning, Psychological / Q000502:physiology; D004192:Discrimination, Psychological / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005625:Frontal Lobe / Q000000981:diagnostic imaging / Q000503:physiopathology*; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000172:deficiency* / Q000235:genetics; D007266:Inhibition, Psychological; D008607:Intellectual Disability / Q000000981:diagnostic imaging / Q000503:physiopathology* / Q000523:psychology; D008297:Male; D018345:Mice, Knockout; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000503:physiopathology*; D009434:Neural Pathways / Q000000981:diagnostic imaging / Q000503:physiopathology; D011897:Random Allocation; D013572:Synaptic Vesicles / Q000378:metabolism; D013998:Time Perception / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: C086796:GDP dissociation inhibitor 1; D020730:Guanine Nucleotide Dissociation Inhibitors; D004298:Dopamine
keywords: Gdi1-null mice; X-linked Intellectual Disability; appetitive conditioning; excitatory synapses; fronto-striatal synaptic plasticity