p21-Activated Kinases 1 and 3 Control Brain Size through Coordinating Neuronal Complexity and Synaptic Properties

Abstract

The molecular mechanisms that coordinate postnatal brain enlargement, synaptic properties, and cognition remain an enigma. Here, we demonstrate that neuronal complexity controlled by p21-activated kinases (PAKs) is a key determinant for postnatal brain enlargement and synaptic properties. We showed that double-knockout (DK) mice lacking both PAK1 and PAK3 were born healthy, with normal brain size and structure, but severely impaired in postnatal brain growth, resulting in a dramatic reduction in brain volume. Remarkably, the reduced brain size was accompanied by minimal changes in total cell count, due to a significant increase in cell density. However, the DK neurons have smaller soma, markedly simplified dendritic arbors/axons, and reduced synapse density. Surprisingly, the DK mice had elevated basal synaptic responses due to enhanced individual synaptic potency but were severely impaired in bidirectional synaptic plasticity. The actions of PAK1 and PAK3 are possibly mediated by cofilin-dependent actin regulation, because the activity of cofilin and the properties of actin filaments were altered in the DK mice. These results reveal an essential in vivo role of PAK1 and PAK3 in coordinating neuronal complexity and synaptic properties and highlight the critical importance of dendrite/axon growth in dictating postnatal brain growth and attainment of normal brain size and function.

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Getting Smart about p21-Activated Kinases

ACKNOWLEDGMENTS

This work was supported by grants from the Canadian Institutes of Health Research (CIHR MOP-42396) (Z.J.), Ontario Mental Health Foundation (Z.J.), and the National Basic Research Program (China, 973 Program, 2005CB522501) (W.X.). Wayne Huang was supported by studentships from NSERC and the Hospital for Sick Children research training center.

We are grateful to Cindy Chiang, Alex Han, Christine Laliberté, Matthijs van Eede, and members of the Jia laboratory for technical assistance and comments on the manuscript. The PAK2 and PAK3 cDNA plasmids were kindly provided by Jonathan Chernoff, David Rubinsztein, and Jean-Vianney Barnier.