DISC1
Disrupted in schizophrenia 1 protein [KIAA0457]
Publications[править]
Current hypotheses stipulate core symptoms of schizophrenia (SZ) result from the brain's incapacity to integrate neural processes. Converging diffusion magnetic resonance imaging and graph theory studies provide evidence of macrostructural alterations in SZ. However, age-related topological changes within and between white matter (WM) networks and its relationship to gene expression with disease progression remain incompletely understood. This cross-sectional study uses network modeling to investigate changes in WM network organization with disease progression in chronic SZ as well its relationship with gene expression in healthy brains. First, we replicate prior findings demonstrating altered global WM network topology in SZ. Novel results show significantly altered age-related network degradation patterns in patients compared with controls. Specifically, controls show stereotyped, linear global network decline with age. In contrast, patients show nonlinear network decline with age. Further analysis reveals lack of significant topological decline in younger adult patients, which is subsequently followed by stereotyped linear decline in older adult patients. Node-specific analyses show significant topological differences in frontal and limbic regions of younger adult patients compared with age-matched controls, which become less pronounced with age in older adult patients compared with age-matched controls. Lastly, we show several gene expression profiles, including DISC1, are associated with age-related changes in WM disconnectivity. Together, these findings provide novel WM topological and genetic evidence supporting neurodevelopmental models of SZ, suggesting that network remodeling continues throughout the third decade of life before stabilizing.
MeSH Terms
- Adult
- Age Factors
- Aging
- Anisotropy
- Cross-Sectional Studies
- Dysbindin
- Female
- Gene Expression
- Humans
- Image Processing, Computer-Assisted
- Magnetic Resonance Imaging
- Male
- Microarray Analysis
- Middle Aged
- Models, Neurological
- Nerve Tissue Proteins
- Neural Pathways
- Receptors, Dopamine D2
- Receptors, Metabotropic Glutamate
- Schizophrenia
- White Matter
- Young Adult
Keywords
- degeneration
- diffusion tensor imaging
- graph theory
- neural networks
- schizophrenia
Histone Deacetylase 11 (HDAC11) is highly expressed in the central nervous system where it has been reported to have roles in neural differentiation. In contrast with previous studies showing nuclear and cytoplasmic localisation, we observed synaptic enrichment of HDAC11. Knockout mouse models for HDACs 1-9 have been important for guiding the development of isoform specific HDAC inhibitors as effective therapeutics. Given the close relationship between HDAC11 and neural cells in vitro, we examined neural tissue in a previously uncharacterised Hdac11 knockout mouse (Hdac11 ). Loss of HDAC11 had no obvious impact on brain morphology and neural stem/precursor cells isolated from Hdac11 mice had comparable proliferation and differentiation characteristics. However, in differentiating neural cells we observed decreased expression of schizophrenia-associated gene Fez1 (fasciculation and elongation protein zeta 1), a gene previously reported to be regulated by HDAC11 activity. FEZ1 has been associated with the dendritic growth of neurons and risk of schizophrenia via its interaction with DISC1 (disrupted in schizophrenia 1). Examination of cortical, cerebellar and hippocampal tissue reveal decreased Fez1 expression specifically in the hippocampus of adult mice. The results of this study demonstrate that loss of HDAC11 has age dependent and brain-region specific consequences.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Aging
- Animals
- Cell Line
- Gene Expression Regulation
- Hippocampus
- Histone Deacetylases
- Mice
- Mice, Knockout
- Nerve Tissue Proteins
- Neural Stem Cells
- Neurogenesis
- Schizophrenia
Drug discovery in psychiatry has been limited to chemical modifications of compounds originally discovered serendipitously. Therefore, more mechanism-oriented strategies of drug discovery for mental disorders are awaited. Schizophrenia is a devastating mental disorder with synaptic disconnectivity involved in its pathophysiology. Reduction in the dendritic spine density is a major alteration that has been reproducibly reported in the cerebral cortex of patients with schizophrenia. Disrupted-in-Schizophrenia-1 (DISC1), a factor that influences endophenotypes underlying schizophrenia and several other neuropsychiatric disorders, has a regulatory role in the postsynaptic density in association with the NMDA-type glutamate receptor, Kalirin-7, and Rac1. Prolonged knockdown of DISC1 leads to synaptic deterioration, reminiscent of the synaptic pathology of schizophrenia. Thus, we tested the effects of novel inhibitors to p21-activated kinases (PAKs), major targets of Rac1, on synaptic deterioration elicited by knockdown expression of DISC1. These compounds not only significantly ameliorated the synaptic deterioration triggered by DISC1 knockdown but also partially reversed the size of deteriorated synapses in culture. One of these PAK inhibitors prevented progressive synaptic deterioration in adolescence as shown by in vivo two-photon imaging and ameliorated a behavioral deficit in prepulse inhibition in adulthood in a DISC1 knockdown mouse model. The efficacy of PAK inhibitors may have implications in drug discovery for schizophrenia and related neuropsychiatric disorders in general.
MeSH Terms
- Aging
- Animals
- Behavior, Animal
- Dendritic Spines
- Disease Models, Animal
- Gene Knockdown Techniques
- Mice
- Nerve Tissue Proteins
- Neuronal Plasticity
- Prefrontal Cortex
- Protein Kinase Inhibitors
- Pyridones
- Pyrimidines
- RNA Interference
- Rats
- Receptors, N-Methyl-D-Aspartate
- Schizophrenia
- Synapses
- p21-Activated Kinases
Keywords
- mechanism-oriented drug discovery
- synapse protection