Loss of Either Rac1 or Rac3 GTPase Differentially Affects the Behavior of Mutant Mice and the Development of Functional GABAergic Networks

Abstract

Rac GTPases regulate the development of cortical/hippocampal GABAergic interneurons by affecting the early development and migration of GABAergic precursors. We have addressed the function of Rac1 and Rac3 proteins during the late maturation of hippocampal interneurons. We observed specific phenotypic differences between conditional Rac1 and full Rac3 knockout mice. Rac1 deletion caused greater generalized hyperactivity and cognitive impairment compared with Rac3 deletion. This phenotype matched with a more evident functional impairment of the inhibitory circuits in Rac1 mutants, showing higher excitability and reduced spontaneous inhibitory currents in the CA hippocampal pyramidal neurons. Morphological analysis confirmed a differential modification of the inhibitory circuits: deletion of either Rac caused a similar reduction of parvalbumin-positive inhibitory terminals in the pyramidal layer. Intriguingly, cannabinoid receptor-1-positive terminals were strongly increased only in the CA1 of Rac1-depleted mice. This increase may underlie the stronger electrophysiological defects in this mutant. Accordingly, incubation with an antagonist for cannabinoid receptors partially rescued the reduction of spontaneous inhibitory currents in the pyramidal cells of Rac1 mutants. Our results show that Rac1 and Rac3 have independent roles in the formation of GABAergic circuits, as highlighted by the differential effects of their deletion on the late maturation of specific populations of interneurons.

Identification of a Protein Network Driving Neuritogenesis of MGE-Derived GABAergic Interneurons

“…In this direction, we have addressed the role of Rac GTPases in the development of these cells. Based on recent findings that Rac's are essential players for the correct development of cortical and hippocampal GABAergic cells in vivo (Vaghi et al, 2014; Tivodar et al, 2015; Pennucci et al, 2016), we have confirmed here that depletion of the endogenous Rac‘s impairs the neuritogenesis of interneurons in vitro .…”

“…Our previous works has shown that Rac1 represented approximately 92% and Rac3 8% of total Rac proteins in P7 mouse brain (Corbetta et al, 2009). Analysis in vivo has shown that single and double Rac knockout affects the development of cortical and hippocampal interneurons (Vaghi et al, 2014; Tivodar et al, 2015; Pennucci et al, 2016). Here we have tested the effects of Rac deletion on the maturation of MGE-derived interneurons in vitro .…”

“…In this respect, recent results have shown that the two Rac GTPases expressed during neuronal development, Rac1 and Rac3, are important for the development of MGE-derived cortical and hippocampal GABAergic interneurons (de Curtis, 2014). Rac1 and Rac3 play a pivotal role in the maturation of MGE-derived cortical and hippocampal interneurons, since the deletion of either Rac1 or Rac3 has negative effects on the maturation and formation of inhibitory synapses by GABAergic cells, with behavioral consequences that include generalized hyperactivity, and cognitive as well as functional impairment of the inhibitory circuits (Pennucci et al, 2016). …”

Retracted: MicroRNA‑224 promotes the sensitivity of osteosarcoma cells to cisplatin by targeting Rac1

“…Rac1 is a member of the Ras superfamily of Rho proteins, and it plays an essential role in many cellular processes, including mitogenesis, kinase cascade activation, transcriptional activation, DNA synthesis and cytoskeleton reorganization [37][38][39][40][41][42]. Rac1 overexpression has been found in various types of cancer, such as lung cancer, gastric cancer, pancreatic cancer, bladder cancer and breast cancer [43][44][45][46][47].…”

Enhancing cognition through pharmacological and environmental interventions: Examples from preclinical models of neurodevelopmental disorders

“…In addition, it is important to note that apart from genetic defects, many other types of manipulations have been used to show that a vast array of early developmental challenges result in profuse long-term neural and cognitive effects (such as on dendritic spine density, brain volume, and attention and working memory) that last well into adulthood; when delayed or presented in adulthood, similar manipulations have less pronounced effect. Such manipulations include brain insults during gestation, parturition or the early postnatal period, as well as altered maternal care and post-weaning isolation, maternal malnutrition and vitamins deficiencies, or early pharmacological treatments (Cope et al, 2016a;Cope et al, 2016b;Lipska et al, 2002a;Lipska et al, 2002b;Lipska et al, 1992;Lipska et al, 2001;Pennucci et al, 2016).…”