title: GlyT-1 Inhibition Attenuates Attentional But Not Learning or Motivational Deficits of the Sp4 Hypomorphic Mouse Model Relevant to Psychiatric Disorders.
abstract: Serious mental illness occurs in 25% of the general population, with many disorders being neurodevelopmental, lifelong, and debilitating. The wide variation and overlap in symptoms across disorders increases the difficulty of research and treatment development. The NIMH Research Domain of Criteria initiative aims to improve our understanding of the molecular and behavioral consequences of specific neurodevelopmental mechanisms across disorders, enabling targeted treatment development. The transcription factor Specificity Protein 4 (SP4) is important for neurodevelopment and is genetically associated with both schizophrenia and bipolar disorder. Reduced Sp4 expression in mice (hypomorphic) reproduces several characteristics of psychiatric disorders. We further tested the utility of Sp4 hypomorphic mice as a model organism relevant to psychiatric disorders by assessing cognitive control plus effort and decision-making aspects of approach motivation using cross-species-relevant tests. Sp4 hypomorphic mice exhibited impaired attention as measured by the 5-Choice Continuous Performance Test, an effect that was attenuated by glycine type-1 transporter (GlyT-1) inhibition. Hypomorphic mice also exhibited reduced motivation to work for a reward and impaired probabilistic learning. These deficits may stem from affected anticipatory reward, analogous to anhedonia in patients with schizophrenia and other psychiatric disorders. Neither positive valence deficit was attenuated by GlyT-1 treatment, suggesting that these and the attentional deficits stem from different underlying mechanisms. Given the association of SP4 gene with schizophrenia and bipolar disorder, the present studies provide support that personalized GlyT-1 inhibition may treat attentional deficits in neuropsychiatric patients with low SP4 levels.
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.|Research Service, VA San Diego Healthcare System, San Diego, CA, USA.
authors.forename: Jared W
authors.initials: JW
authors.lastname: Young
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Kamenski
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Kerin K
authors.identifier: http://orcid.org/0000-0002-0513-6164
authors.initials: KK
authors.lastname: Higa
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.|Research Service, VA San Diego Healthcare System, San Diego, CA, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Light
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.|Research Service, VA San Diego Healthcare System, San Diego, CA, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Geyer
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.|Research Service, VA San Diego Healthcare System, San Diego, CA, USA.
authors.forename: Xianjin
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000209:etiology; D002755:Choice Behavior / Q000187:drug effects; D004195:Disease Models, Animal; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D050487:Glycine Plasma Membrane Transport Proteins / Q000378:metabolism*; D007859:Learning Disabilities / Q000188:drug therapy / Q000209:etiology; D008297:Male; D001523:Mental Disorders / Q000150:complications / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019964:Mood Disorders / Q000188:drug therapy / Q000209:etiology; D009042:Motivation / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D011337:Probability Learning; D051706:Sp4 Transcription Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D050487:Glycine Plasma Membrane Transport Proteins; C493267:Slc6a9 protein, mouse; D051706:Sp4 Transcription Factor; C435781:org 24598; D005998:Glycine