Rac1 and Rac3 GTPases Control Synergistically the Development of Cortical and Hippocampal GABAergic Interneurons

Abstract

The intracellular mechanisms driving postmitotic development of cortical γ-aminobutyric acid (GABA)ergic interneurons are poorly understood. We have addressed the function of Rac GTPases in cortical and hippocampal interneuron development. Developing neurons express both Rac1 and Rac3. Previous work has shown that Rac1 ablation does not affect the development of migrating cortical interneurons. Analysis of mice with double deletion of Rac1 and Rac3 shows that these GTPases are required during postmitotic interneuron development. The number of parvalbumin-positive cells was affected in the hippocampus and cortex of double knockout mice. Rac depletion also influences the maturation of interneurons that reach their destination, with reduction of inhibitory synapses in both hippocampal CA1 and cortical pyramidal cells. The decreased number of cortical migrating interneurons and their altered morphology indicate a role of Rac1 and Rac3 in regulating the motility of cortical interneurons, thus interfering with their final localization. While electrophysiological passive and active properties of pyramidal neurons including membrane capacity, resting potential, and spike amplitude and duration were normal, these cells showed reduced spontaneous inhibitory currents and increased excitability. Our results show that Rac1 and Rac3 contribute synergistically to postmitotic development of specific populations of GABAergic cells, suggesting that these proteins regulate their migration and differentiation.

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 .…”

Rho GTPases in embryonic development

“…58,63 The recent study by Vaghi et al (2012) investigating Rac1 and the neural specific Rac3 in the development of cortical and hippocampal GABAergic neurons suggests that both Rac1 and Rac3 contribute synergistically to the regulation of cortical and hippocampal neuronal migration and differentiation, which may explain the epileptic phenotype of the Rac1/Rac3 double mutant mice. 64,65 Lastly, several defects were also observed in the development of the cerebellum lacking Rac1. 66 Taken together, these studies clearly establish fundamental roles of RhoA, Rac1, and Cdc42 during early development of the CNS.…”

Rho GTPase isoforms in cell motility: Don't fret, we have FRET

“…99 In contrast, Rac3 and Rac1 appear to perform synergistic roles in the development of the nervous system as loss of both isoforms results in defects in the migration and differentiation of a number of brain cell types. [100][101][102][103] Loss of either isoform in the brain does not lead to obvious defects. 100 These results highlight that each of the Rac isoforms had been specialized for a very particular function and displays its own specific biology.…”