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Brain Struct Funct. 2018 Dec;223(9):4227-4241. doi: 10.1007/s00429-018-1748-4. Epub 2018 Sep 8.

Distinct and complementary functions of rho kinase isoforms ROCK1 and ROCK2 in prefrontal cortex structural plasticity.

Author information

1
Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, 1825 University Blvd., Birmingham, AL, 35294, USA.
2
Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, 1825 University Blvd., Birmingham, AL, 35294, USA. jhersko@uab.edu.

Abstract

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.

KEYWORDS:

Dendritic arbor; Dendritic spines; LIM kinase; Morphometry; Prefrontal cortex; Rho kinase; Synaptosomes

PMID:
30196430
PMCID:
PMC6252131
[Available on 2019-12-01]
DOI:
10.1007/s00429-018-1748-4

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