PAKs 1 and 3 control postnatal brain growth and function through regulation of axonal and dendritic arborization.
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1
University of Toronto, Department of Physiology, Canada
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2
The Hospital for Sick Children, Mouse Imaging Centre, Canada
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3
The Hospital for Sick Children, Neurosciences and Mental Health, Canada
The underlying mechanisms that coordinate postnatal development of brain size with development of intellectual capacity remain an enigma. In this study, we provide evidence indicating that the axonal and dendritic arborization is a key determinant of postnatal brain growth and function. The double knockout mice lacking expression of both P-21 Activated Kinases (PAKs) 1 and 3, key regulators of cytoskeletal dynamics, were born healthy with normal brain size but displayed impaired postnatal brain growth, resulting in a notable reduction of brain volume at maturity (64% of WT). Stereology revealed that the reduced brain size in the mutant mice is accompanied by little changes in the total cell count due to a proportional increase in the density of brain cells. However, neurons lacking PAK1&3 developed smaller soma, and drastically simplified dendritic and axonal arborization. Based on electron micrograph data and regional volume reductions shown by MRI, we estimated a 50% reduction in synapse number in the mutant brain as a direct consequence of the reduced arborization. This reduction in synapse number was accompanied by enlargement of individual synapses and altered synaptic architecture. Consistent with the structural changes, the PAK1&3 knockout mice displayed profound abnormalities in basal synaptic transmission and excitability, as well as in synaptic plasticity. At the behavioral level, the mutant mice exhibited hyper-anxiety, hyper-activity and nearly abolished fear and spatial learning – a striking resemblance to the clinical phenotype of PAK3-associated X-linked mental retardation patients. Our results suggest that PAK signalling regulates postnatal maturation of both brain size and cognitive functions, through actin-mediated neuronal morphogenesis.
This study was funded by CIHR, NSERC and the Hospital for Sick Children Restracomp Award.
Conference:
B.R.A.I.N. platform in Physiology poster day 2009, Toronto, ON, Canada, 16 Dec - 16 Dec, 2009.
Presentation Type:
Oral Presentation
Topic:
Oral presentations
Citation:
Huang
W,
Henkelman
M,
H
H and
Jia
Z
(2009). PAKs 1 and 3 control postnatal brain growth and function through regulation of axonal and dendritic arborization..
Front. Neurosci.
Conference Abstract:
B.R.A.I.N. platform in Physiology poster day 2009.
doi: 10.3389/conf.neuro.03.2009.17.023
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Received:
17 Dec 2009;
Published Online:
17 Dec 2009.
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Correspondence:
Wayne Huang, University of Toronto, Department of Physiology, Toronto, Canada, wayne.huang@utoronto.ca