%0 Journal Article
%T Developmental RacGAP ¦Á2-Chimaerin Signaling Is a Determinant of the Morphological Features of Dendritic Spines in Adulthood
%A Hidenobu Mizuno
%A Hiroshi Matsukawa
%A Kosuke Yasuda
%A Ryohei Iwata
%A Shigeyoshi Itohara
%A Takuji Iwasato
%J The Journal of Neurosience
%D 2015
%R 10.1523/JNEUROSCI.0419-15.2015
%X Morphological characteristics of dendritic spines form the basis of cognitive ability. However, molecular mechanisms involved in fine-tuning of spine morphology during development are not fully understood. Moreover, it is unclear whether, and to what extent, these developmental mechanisms determine the normal adult spine morphological features. Here, we provide evidence that ¦Á2-isoform of Rac-specific GTPase-activating protein ¦Á-chimaerin (¦Á2-chimaerin) is involved in spine morphological refinement during late postnatal period, and furthermore show that this developmental ¦Á2-chimaerin function affects adult spine morphologies. We used a series of mice with global and conditional knock-out of ¦Á-chimaerin isoforms (¦Á1-chimaerin and ¦Á2-chimaerin). ¦Á2-Chimaerin disruption, but not ¦Á1-chimaerin disruption, in the mouse results in an increased size (and density) of spines in the hippocampus. In contrast, overexpression of ¦Á2-chimaerin in developing hippocampal neurons induces a decrease of spine size. Disruption of ¦Á2-chimaerin suppressed EphA-mediated spine morphogenesis in cultured developing hippocampal neurons. ¦Á2-Chimaerin disruption that begins during the juvenile stage results in an increased size of spines in the hippocampus. Meanwhile, spine morphologies are unaltered when ¦Á2-chimaerin is deleted only in adulthood. Consistent with these spine morphological results, disruption of ¦Á2-chimaerin beginning in the juvenile stage led to an increase in contextual fear learning in adulthood; whereas contextual learning was recently shown to be unaffected when ¦Á2-chimaerin was deleted only in adulthood. Together, these results suggest that ¦Á2-chimaerin signaling in developmental stages contributes to determination of the morphological features of adult spines and establishment of normal cognitive ability.

SIGNIFICANCE STATEMENT Recent studies of neurodevelopmental disorders in humans and their animal models have led to an attractive hypothesis that spine morphogenesis during development forms the basis of adult cognition. In particular, the roles of Rac and its regulators, such as Rac-specific GTPase-activating proteins (RacGAPs) and Rac guanine nucleotide exchange factors, are a topic of focus in spine morphogenesis and cognitive ability. Using a series of mice with global and conditional knock-out (KO) of RacGAP ¦Á-chimaerin isoforms (¦Á1-chimaerin and ¦Á2-chimaerin), we provide compelling evidence demonstrating that ¦Á2-chimaerin is involved in spine morphological refinement during late postnatal development and that this developmental ¦Á2-chimaerin function
%U http://www.jneurosci.org/content/35/40/13728