期刊
BRAIN STRUCTURE & FUNCTION
卷 223, 期 9, 页码 4227-4241出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00429-018-1748-4
关键词
Rho kinase; LIM kinase; Dendritic spines; Prefrontal cortex; Dendritic arbor; Morphometry; Synaptosomes
资金
- National Institutes of Health [NIA AG061800, NIA AG054719, NIA AG043552]
- Alzheimer's Association [2015-NIRG-339422]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [T32NS061788] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG054719, R00AG043552, R01AG061800, K99AG043552] Funding Source: NIH RePORTER
Rho-associated protein kinases (ROCK) 1 and 2 are attractive drug targets for a range of neurologic disorders; however, a critical barrier to ROCK-based therapeutics is ambiguity over whether there are isoform-specific roles for ROCKs in neuronal structural plasticity. Here, we used a genetics approach to address this long-standing question by analyzing both male and female adult ROCK1(+/-) and ROCK2(+/-) mice compared to littermate controls. Individual pyramidal neurons in the medial prefrontal cortex (mPFC) were targeted for iontophoretic microinjection of fluorescent dye, followed by high-resolution confocal microscopy and neuronal 3D reconstructions for morphometry analysis. Increased apical and basal dendritic length and intersections were observed in ROCK1(+/-) but not ROCK2(+/-) mice. Although dendritic spine densities were comparable among genotypes, apical spine length was decreased in ROCK1(+/-) but increased in ROCK2(+/-) mice. Spine head and neck diameter were reduced similarly in ROCK1(+/-) and ROCK2(+/-) mice; however, certain spine morphologic subclasses were more affected than others in a genotype-dependent manner. Biochemical analyses of ROCK substrates in synaptic fractions revealed that phosphorylation of LIM kinase and cofilin were reduced in ROCK1(+/-) and ROCK2(+/-) mice, while phosphorylation of myosin light chain was decreased exclusively in ROCK1(+/-) mice. Collectively, these observations implicate ROCK1 as a novel regulatory factor of neuronal dendritic structure and detail distinct and complementary roles of ROCKs in mPFC dendritic spine structure.
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