OBJECTIVE: Lower dendritic spine density on layer 3 pyramidal cells in the dorsolateral prefrontal cortex (DLPFC) appears to contribute to cognitive dysfunction in schizophrenia, whereas psychosis is associated with excessive dopamine release in the striatum. These findings may be related via excitatory projections from the DLPFC to the ventral mesencephalon, the location of dopamine cells projecting to the striatum. Consistent with this hypothesis, deletion of the actin-related protein-2/3 (ARP2/3) complex, which regulates the actin cytoskeleton supporting dendritic spines, produced spine loss in cortical pyramidal cells and striatal hyperdopaminergia in mice. The authors sought to determine whether the ARP2/3 complex is altered in schizophrenia. METHOD: In matched pairs of schizophrenia and comparison subjects, transcript levels of ARP2/3 complex signaling pathway were assessed in laser-microdissected DLPFC layer 3 and 5 pyramidal cells and layer 3 parvalbumin interneurons, and in total DLPFC gray matter. RESULTS: Transcript levels of ARP2/3 complex subunits and of nucleation promotion factors that regulate the ARP2/3 complex were significantly lower in DLPFC layer 3 and 5 pyramidal cells in schizophrenia. In contrast, these transcripts were unaltered, or only modestly changed, in parvalbumin interneurons and DLPFC gray matter. CONCLUSIONS: Down-regulation of the ARP2/3 complex signaling pathway, a common final pathway for multiple signaling cascades that regulate the actin cytoskeleton, would compromise the structural stability of spines, leading to their loss. In concert with findings from deletion of the ARP2/3 complex in mice, these findings support the idea that spine deficits in the DLPFC may contribute to subcortical hyperdopaminergia in schizophrenia.
OBJECTIVE: Lower dendritic spine density on layer 3 pyramidal cells in the dorsolateral prefrontal cortex (DLPFC) appears to contribute to cognitive dysfunction in schizophrenia, whereas psychosis is associated with excessive dopamine release in the striatum. These findings may be related via excitatory projections from the DLPFC to the ventral mesencephalon, the location of dopamine cells projecting to the striatum. Consistent with this hypothesis, deletion of the actin-related protein-2/3 (ARP2/3) complex, which regulates the actin cytoskeleton supporting dendritic spines, produced spine loss in cortical pyramidal cells and striatal hyperdopaminergia in mice. The authors sought to determine whether the ARP2/3 complex is altered in schizophrenia. METHOD: In matched pairs of schizophrenia and comparison subjects, transcript levels of ARP2/3 complex signaling pathway were assessed in laser-microdissected DLPFC layer 3 and 5 pyramidal cells and layer 3 parvalbumin interneurons, and in total DLPFC gray matter. RESULTS: Transcript levels of ARP2/3 complex subunits and of nucleation promotion factors that regulate the ARP2/3 complex were significantly lower in DLPFC layer 3 and 5 pyramidal cells in schizophrenia. In contrast, these transcripts were unaltered, or only modestly changed, in parvalbumin interneurons and DLPFC gray matter. CONCLUSIONS: Down-regulation of the ARP2/3 complex signaling pathway, a common final pathway for multiple signaling cascades that regulate the actin cytoskeleton, would compromise the structural stability of spines, leading to their loss. In concert with findings from deletion of the ARP2/3 complex in mice, these findings support the idea that spine deficits in the DLPFC may contribute to subcortical hyperdopaminergia in schizophrenia.
Authors: James P Clement; Massimiliano Aceti; Thomas K Creson; Emin D Ozkan; Yulin Shi; Nicholas J Reish; Antoine G Almonte; Brooke H Miller; Brian J Wiltgen; Courtney A Miller; Xiangmin Xu; Gavin Rumbaugh Journal: Cell Date: 2012-11-09 Impact factor: 41.582
Authors: Ruben C Gur; Monica E Calkins; Theodore D Satterthwaite; Kosha Ruparel; Warren B Bilker; Tyler M Moore; Adam P Savitt; Hakon Hakonarson; Raquel E Gur Journal: JAMA Psychiatry Date: 2014-04 Impact factor: 21.596
Authors: G Kirov; A J Pocklington; P Holmans; D Ivanov; M Ikeda; D Ruderfer; J Moran; K Chambert; D Toncheva; L Georgieva; D Grozeva; M Fjodorova; R Wollerton; E Rees; I Nikolov; L N van de Lagemaat; A Bayés; E Fernandez; P I Olason; Y Böttcher; N H Komiyama; M O Collins; J Choudhary; K Stefansson; H Stefansson; S G N Grant; S Purcell; P Sklar; M C O'Donovan; M J Owen Journal: Mol Psychiatry Date: 2011-11-15 Impact factor: 15.992
Authors: Matthew L MacDonald; Daley Favo; Megan Garver; Zhe Sun; Dominique Arion; Ying Ding; Nathan Yates; Robert A Sweet; David A Lewis Journal: Neuropsychopharmacology Date: 2018-11-02 Impact factor: 7.853
Authors: Avanti Gokhale; Cortnie Hartwig; Amanda H Freeman; Ravi Das; Stephanie A Zlatic; Rachel Vistein; Amelia Burch; Guillemette Carrot; Arielle F Lewis; Sheldon Nelms; Dion K Dickman; Manojkumar A Puthenveedu; Daniel N Cox; Victor Faundez Journal: J Neurosci Date: 2016-12-07 Impact factor: 6.167
Authors: Cortnie Hartwig; William J Monis; Xun Chen; Dion K Dickman; Gregory J Pazour; Victor Faundez Journal: Dev Neurobiol Date: 2017-10-13 Impact factor: 3.964
Authors: Il Hwan Kim; Namsoo Kim; Sunwhi Kim; Koji Toda; Christina M Catavero; Jamie L Courtland; Henry H Yin; Scott H Soderling Journal: Cell Rep Date: 2020-07-28 Impact factor: 9.995