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Mol Cell Neurosci. 2019 Jul;98:1-11. doi: 10.1016/j.mcn.2019.04.002. Epub 2019 Apr 13.

Klotho deficiency affects the spine morphology and network synchronization of neurons.

Author information

1
Department of Neurobiology, University of Alabama at Birmingham, 1825 University Blvd. Shelby 913, Birmingham 35294, AL, USA.
2
Department of Neurology, University of Alabama at Birmingham, 1825 University Blvd. Shelby 1114, Birmingham 35294, AL, USA.
3
Department of Neurobiology, University of Alabama at Birmingham, 1825 University Blvd. Shelby 913, Birmingham 35294, AL, USA. Electronic address: gdking@uab.edu.

Abstract

Klotho-deficient mice rapidly develop cognitive impairment and show some evidence of the onset of neurodegeneration. However, it is impossible to investigate the long-term consequences on the brain because of the dramatic shortening of lifespan caused by systemic klotho deficiency. As klotho expression is downregulated with advancing organismal age, understanding the mechanisms of klotho action is important for developing novel strategies to support healthy brain aging. Previously, we reported that klotho-deficient mice show enhanced long-term potentiation prior to the onset of cognitive impairment. To inform this unusual phenotype, herein, we examined neuronal structure and in vitro synaptic function. Our results indicate that klotho deficiency causes the population of dendritic spines to shift towards increased head diameter and decreased length consistent with mature, mushroom type spines. Multi-electrode array recordings from klotho-deficient neurons show increased synchronous firing and activity changes reflective of increased neuronal network activity. Supplementation of the neuronal growth media with recombinant shed klotho corrected some but not all of the activity changes caused by klotho deficiency. Last, in vivo we found that klotho-deficient mice have a decreased latency to induced seizure activity. Together these data show that klotho-deficient memory impairments are underpinned by structural and functional changes that may preclude ongoing normal cognition.

KEYWORDS:

Aging; Dendritic spine; Morphology; Multi-electrode array; Pentylenetetrazole

PMID:
30991103
PMCID:
PMC6613977
[Available on 2020-07-01]
DOI:
10.1016/j.mcn.2019.04.002

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