title: Disrupted-in-schizophrenia-1 Gln31Leu polymorphism results in social anhedonia associated with monoaminergic imbalance and reduction of CREB and β-arrestin-1,2 in the nucleus accumbens in a mouse model of depression.
abstract: Disrupted-in-schizophrenia-1 (DISC1) is associated with mental disorders, including major depression. We previously showed that DISC1-Q31L mutant mice have depression-like behaviors and can therefore be used to study neurobiological mechanisms of depression and antidepressant (AD) medication action. First, we found reduced levels of dopamine, serotonin and norepinephrine in the nucleus accumbens (NAC) of DISC1-Q31L mutants. Next, we assessed social-conditioned place preference as a reward-dependent task and the capacity of distinct ADs to correct impaired social behavior in DISC1-Q31L mice. Bupropion, but not fluoxetine or desipramine, was able to correct deficient social facilitation, social reward, and social novelty in DISC1-Q31L mutants, whereas all three ADs were able to improve social motivation and behavioral despair in DISC1-Q31L mutants. Furthermore, we sought to correlate social anhedonia with molecular and cellular features including dendritic spine density, β-arrestin-1,2, and cAMP-response-element-binding protein (CREB) in the NAC as biomarkers related to depression and the DISC1 pathway. DISC1-Q31L mutants showed reduced levels of β-arrestin-1,2, CREB, and spine density in the NAC, further supporting the construct validity of the genetic model. Bupropion induced the greatest effect on CREB in DISC1-Q31L mutants, whereas all studied ADs corrected the reduced levels of β-arrestin-1,2 and modestly ameliorated deficient spine density in this brain region. Overall, we find neurobiological changes accompanying social anhedonia in the NAC of DISC1-Q31L mutant mice, consistent with a role for DISC1 in regulating social reward as an endophenotype of depression.
authors.affiliation: Centre of Neurodevelopment and Cognitive Functions, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Lipina
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fletcher
authors.forename: Frankie H
authors.initials: FH
authors.lastname: Lee
authors.forename: Albert H C
authors.initials: AH
authors.lastname: Wong
authors.forename: John C
authors.initials: JC
authors.lastname: Roder
mesh_terms: D059445:Anhedonia / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D015306:Biogenic Monoamines / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005973:Glutamine / Q000235:genetics; D007930:Leucine / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: D000928:Antidepressive Agents; C000605255:Arrb1 protein, mouse; D019390:Arrestins; D015306:Biogenic Monoamines; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D005973:Glutamine; D007930:Leucine