Developmental RacGAP alpha 2-Chimaerin Signaling Is a Determinant of the Morphological Features of Dendritic Spines in Adulthood

• Published in: The Journal of neuroscience 2015-10, Vol.35 (40), p.13728-13744
• Main Authors: Iwata, Ryohei, Matsukawa, Hiroshi, Yasuda, Kosuke, Mizuno, Hidenobu, Itohara, Shigeyoshi, Iwasato, Takuji
• Format: Article
• Language: English
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.0419-15.2015

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 alpha 2-isoform of Rac-specific GTPase-activating protein alpha -chimaerin ( alpha 2-chimaerin) is involved in spine morphological refinement during late postnatal period, and furthermore show that this developmental alpha 2-chimaerin function affects adult spine morphologies. We used a series of mice with global and conditional knock-out of alpha -chimaerin isoforms ( alpha 1-chimaerin and alpha 2-chimaerin). alpha 2-Chimaerin disruption, but not alpha 1-chimaerin disruption, in the mouse results in an increased size (and density) of spines in the hippocampus. In contrast, overexpression of alpha 2-chimaerin in developing hippocampal neurons induces a decrease of spine size. Disruption of alpha 2-chimaerin suppressed EphA-mediated spine morphogenesis in cultured developing hippocampal neurons. alpha 2-Chimaerin disruption that begins during the juvenile stage results in an increased size of spines in the hippocampus. Meanwhile, spine morphologies are unaltered when alpha 2-chimaerin is deleted only in adulthood. Consistent with these spine morphological results, disruption of alpha 2-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 alpha 2-chimaerin was deleted only in adulthood. Together, these results suggest that alpha 2-chimaerin signaling in developmental stages contributes to determination of the morphological features of adult spines and establishment of normal cognitive ability.