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 doubleknockout (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.

Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486

“…More specifically, dnPAK targets the autoinhibitory domain of group I PAKs, but does not inhibit group II PAKs. The former group consists of three isoforms-PAK1, PAK2, and PAK3-which are enriched in the brain and critical for brain growth and proper cognitive function (32)(33)(34).…”

Developmental regulation of hippocampal long-term depression by cofilin-mediated actin reorganization

“…We and others have previously shown that cofilin-dependent actin changes are required for spine regulation and hippocampal plasticity, in particular LTD (Meng et al, 2002;Jia et al, 2009;Rust et al, 2010;Huang et al, 2011;Eales et al, 2014;Todorovski et al, 2015;Liu et al, 2016), but whether its involvement in these processes is developmentally regulated remains unknown. This is an important question because LTD is strongly affected by the developmental stages of the brain (Kemp et al, 1999;Fitzjohn et al, 2001).…”

“…5A 5C, Ctrl: 65.3±8.0%, n=8; phalloidin: 98.6 ± 8.4%, n = 8; p<0.05). To determine if the effect of phalloidin is mediated by cofilin-dependent actin reorganization, we tested two cofilin peptides S3 and pS3 known to increase and decrease cofilin activity respectively (Aizawa et al, 2001;Huang et al, 2011). As shown in Fig.…”

“…In this regard, we and others have previously shown that Rho GTPase-activated protein kinases, including p21-activated kinases (PAK1 and 3), Rho-kinase 2 (ROCK2) and LIM-domain containing kinase (LIMK1), are critically involved in both LTP, LTD and associated spine plasticity (Meng et al, 2002(Meng et al, , 2004Meng et al, 2005;Asrar et al, 2009;Zhou et al, 2009;Huang et al, 2011;Bosch et al, 2014;Todorovski et al, 2015;Nishiyama and Yasuda, 2015). Importantly, these kinases all target cofilin, a potent regulator of the actin cytoskeleton (Bernstein and Bamburg, 2010), suggesting that cofilin-mediated actin reorganization may serve as a common effector to mediate, and potentially coordinate functional and morphological changes during synaptic remodeling (Meng et al, 2003a;Jia et al,2009;Asrar and Jia, 2013;Rust, 2015).…”

Identification of neuronal substrates implicates Pak5 in synaptic vesicle trafficking

“…Loss of Pak3 expression as well as specific mutations in PAK3 are associated with abnormalities in synaptic plasticity and cognition (6,7) and a decreased density of dendritic spines (8). In addition, both Pak1 and Pak3 are involved in regulating brain mass through modulation of neuronal size and synaptic complexity (9). These findings underscore the need to further characterize the roles of protein kinases, particularly those of the Pak family, in neuronal physiology and pathology.…”