title: Disrupted in schizophrenia 1 (DISC1) L100P mutants have impaired activity-dependent plasticity in vivo and in vitro.
abstract: Major neuropsychiatric disorders are genetically complex but share overlapping etiology. Mice mutant for rare, highly penetrant risk variants can be useful in dissecting the molecular mechanisms involved. The gene disrupted in schizophrenia 1 (DISC1) has been associated with increased risk for neuropsychiatric conditions. Mice mutant for Disc1 display morphological, functional and behavioral deficits that are consistent with impairments observed across these disorders. Here we report that Disc1 L100P mutants are less able to reorganize cortical circuitry in response to stimulation in vivo. Molecular analysis reveals that the mutants have a reduced expression of PSD95 and pCREB in visual cortex and fail to adjust expression of such markers in response to altered stimulation. In vitro analysis shows that mutants have impaired functional reorganization of cortical neurons in response to selected forms of neuronal stimulation, but there is no altered basal expression of synaptic markers. These findings suggest that DISC1 has a critical role in the reorganization of cortical plasticity and that this phenotype becomes evident only under challenge, even at early postnatal stages. This result may represent an important etiological mechanism in the emergence of neuropsychiatric disorders.
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.|Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.|Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Tropea
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.|Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
authors.forename: I
authors.initials: I
authors.lastname: Molinos
authors.affiliation: Department of Molecular and Cellular Therapeutics, Royal College of Surgeon in Ireland, Dublin, Ireland.
authors.forename: E
authors.initials: E
authors.lastname: Petit
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.|Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
authors.forename: S
authors.initials: S
authors.lastname: Bellini
authors.affiliation: Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Nagakura
authors.affiliation: Department of Molecular and Cellular Therapeutics, Royal College of Surgeon in Ireland, Dublin, Ireland.
authors.forename: C
authors.initials: C
authors.lastname: O'Tuathaigh
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.|Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
authors.forename: L
authors.initials: L
authors.lastname: Schorova
authors.affiliation: Smurfit Institute and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
authors.forename: K J
authors.initials: KJ
authors.lastname: Mitchell
authors.affiliation: Department of Molecular and Cellular Therapeutics, Royal College of Surgeon in Ireland, Dublin, Ireland.
authors.forename: J
authors.initials: J
authors.lastname: Waddington
authors.affiliation: Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sur
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.|Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
authors.forename: M
authors.identifier: http://orcid.org/0000-0003-0206-5337
authors.initials: M
authors.lastname: Gill
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.|Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
authors.forename: A P
authors.initials: AP
authors.lastname: Corvin
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000503:physiopathology*; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009473:Neuronal Plasticity / Q000235:genetics* / Q000502:physiology; D012559:Schizophrenia / Q000235:genetics / Q000503:physiopathology*
chemical_list: C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins