title: Cortical-amygdalar circuit dysfunction in a genetic mouse model of serotonin deficiency.
abstract: Although the majority of first-line antidepressants increase brain serotonin and rare polymorphisms in tryptophan hydroxlase-2 (Tph2), the rate-limiting enzyme in the brain serotonin synthesis pathway, have been identified in cohorts of subjects with major depressive disorder, the circuit level alterations that results from serotonergic hypofunction remain poorly understood. Here we use chronic multicircuit neurophysiological recordings to characterize functional interactions across cortical and limbic circuits in mice engineered to express a human loss-of-function depression allele Tph2-(R441H) [Tph2 knockin (Tph2KI)]. Our results show that Tph2KI mice exhibit increased intra-network synchrony within medial prefrontal cortex (mPFC) and basal amygdala (AMY) and increased inter-network synchrony between these two brain networks. Moreover, we demonstrate that chronic treatment with fluoxetine reverses several of the circuit alterations observed within Tph2KI mice. Together, our findings establish a functional link between functional hyposerotonergia and altered mPFC-AMY network dynamics.
authors: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA. kafui.dzirasa@duke.edu
authors: Kafui
authors: K
authors: Dzirasa
authors: Sunil
authors: S
authors: Kumar
authors: Benjamin D
authors: BD
authors: Sachs
authors: Marc G
authors: MG
authors: Caron
authors: Miguel A L
authors: MA
authors: Nicolelis
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000503:physiopathology*; D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000235:genetics; D001683:Biological Clocks / Q000187:drug effects / Q000235:genetics; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology*; D003863:Depression / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004567:Electrodes, Implanted; D005071:Evoked Potentials / Q000187:drug effects / Q000235:genetics; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use; D019417:Hindlimb Suspension; D006639:Histidine / Q000235:genetics; D006801:Humans; D046353:Immobility Response, Tonic / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009434:Neural Pathways / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000502:physiology; D012701:Serotonin / Q000172:deficiency* / Q000235:genetics; D013057:Spectrum Analysis; D014365:Tryptophan Hydroxylase / Q000235:genetics
chemical_list: D005473:Fluoxetine; D012701:Serotonin; D006639:Histidine; D001120:Arginine; C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase