Pubertal Maturation Modifies the Regulation of Insulin-Like Growth Factor-I Receptor Signaling by Estradiol in the Rat Prefrontal Cortex Amaya Sanz, Paloma Carrero, Olga Pernı´a, Luis M. Garcia-Segura Department of Functional and Systems Neurobiology, Instituto Cajal, CSIC, E-28002 Madrid, Spain Received 2 November 2007; revised 3 March 2008; accepted 4 March 2008 ABSTRACT: The transition from adolescence to adulthood is accompanied by substantial plastic modifi- cations in the cerebral cortex, including changes in the growth and retraction of neuronal processes and in the rate of synaptic formation and neuronal loss. Some of these plastic changes are prevented in female rats by prepubertal ovariectomy. The ovarian hormone estra- diol modulates neuronal differentiation and survival and these effects are in part mediated by the interaction with insulin-like growth factor-I (IGF-I). In this study, we have explored whether the activation by estradiol of some components of IGF-I receptor signaling is altered in the prefrontal cortex during puberty. Estradiol administration to rats ovariectomized after puberty resulted, 24 h after the hormonal administration, in a sustained phosphorylation of Akt and glycogen synthase kinase 3b in the prefrontal cortex. However, this hormo- nal effect was not observed in animals ovariectomized before puberty. These findings suggest that during pubertal maturation there is a programming by ovarian hormones of the future regulatory actions of estradiol on IGF-I receptor signaling in the prefrontal cortex. The modification in the regulation of IGF-I receptor sig- naling by estradiol during pubertal maturation may have implications for the developmental changes occur- ring in the prefrontal cortex in the transition from adolescence to adulthood. ' 2008 Wiley Periodicals, Inc. Develop Neurobiol 68: 1018–1028, 2008 Keywords: adolescence; Akt; neuronal plasticity; estrogen receptors; glycogen synthase kinase 3b INTRODUCTION Pubertal maturation is associated with developmental changes in arousal, motivation, emotion, and cogni- tion (Steinberg, 2005). These changes are sustained by a high degree of brain developmental plasticity. Axons, dendrites, synapses, and synaptic receptors are modified in several brain areas between puberty and adulthood (Sisk and Zehr, 2005). Studies in humans have detected that gray matter volume in several regions of the cerebral cortex does not reach adult steady state until the early to mid 20s (Giedd et al., 1999; Gogtay et al., 2004). In addition, growth rates in fibers innervating association and language cortices are attenuated after puberty (Thompson et al., 2000) and there is a noticeable synaptic pruning during adolescence and early adulthood (Gogtay et al., 2004). Animal studies have also revealed im- portant changes in cortical structure during the time of pubertal maturation. In hippocampal neurons of male rats, the density of dendritic spines increases at puberty onset and then decreases after puberty (Meyer et al., 1978). In the somatosensory cortex of Rhesus monkeys, an overproduction of synapses in infancy is followed by their elimination during ado- lescence and during puberty the synaptic pruning accelerates (Zecevic and Rakic, 1991). Neuronal den- sity is also modified during puberty and adolescence Correspondence to: L.M. Garcia-Segura (lmgs@cajal.csic.es). Contract grant sponsor: Ministerio de Educacio ´n y Ciencia, Spain; contract grant number: SAF 2005-00272. Contract grant sponsor: The European Union (EWA project); contract grant number: LSHM-CT-2005-518245. ' 2008 Wiley Periodicals, Inc. Published online 29 April 2008 in Wiley InterScience (www. interscience.wiley.com). DOI 10.1002/dneu.20641 1018