Inhibition of Rho via Arg and p190RhoGAP in the Postnatal Mouse Hippocampus Regulates Dendritic Spine Maturation, Synapse and Dendrite Stability, and Behavior

Abstract

The RhoA (Rho) GTPase is a master regulator of dendrite morphogenesis. Rho activation in developing neurons slows dendrite branch dynamics, yielding smaller, less branched dendrite arbors. Constitutive activation of Rho in mature neurons causes dendritic spine loss and dendritic regression, indicating that Rho can affect dendritic structure and function even after dendrites have developed. However, it is unclear whether and how endogenous Rho modulates dendrite and synapse morphology after dendrite arbor development has occurred. We demonstrate that a Rho inhibitory pathway involving the Arg tyrosine kinase and p190RhoGAP is essential for synapse and dendrite stability during late postnatal development. Hippocampal CA1 pyramidal dendrites develop normally in arg Ϫ/Ϫ mice, reaching their mature size by postnatal day 21 (P21). However, dendritic spines do not undergo the normal morphological maturation in these mice, leading to a loss of hippocampal synapses and dendritic branches by P42. Coincident with this synapse and dendrite loss, arg Ϫ/Ϫ mice exhibit progressive deficits in a hippocampus-dependent object recognition behavioral task. p190RhoGAP localizes to dendritic spines, and its activity is reduced in arg Ϫ/Ϫ hippocampus, leading to increased Rho activity. Although mutations in p190rhogap enhance dendritic regression resulting from decreased Arg levels, reducing gene dosage of the Rho effector ROCKII can suppress the dendritic regression observed in arg Ϫ/Ϫ mice. Together, these data indicate that signaling through Arg and p190RhoGAP acts late during synaptic refinement to promote dendritic spine maturation and synapse/dendrite stability by attenuating synaptic Rho activity.

Loss of dendrite stabilization by the Abl-related gene (Arg) kinase regulates behavioral flexibility and sensitivity to cocaine

“…The same phenotype has been observed in adolescent rodents tested before or during the period when the dendritic stabilizing effects of Arg are first detectable (10,23). To evaluate the degree to which Arg deficiency recapitulates the adolescent response to cocaine, we tested locomotor activity after repeated cocaine injection in P42 (peri-adolescent) and P180 (adult) mice.…”

“…Recent studies have identified a Rho inhibitory pathway involving integrin adhesion receptors, the Abl family tyrosine kinase, Arg, and the Rho inhibitor, p190RhoGAP, that acts in dendritic spines of late adolescent mice to maintain synapses and promote dendrite stability during maturation into adulthood. Cortical axons, dendrites, and synapses develop normally in Arg-deficient (arg Ϫ/Ϫ ) mice; but dendrites destabilize with age, leading to significant atrophy by 6 weeks (10,11), corresponding to adolescence in humans (12).…”

Abl2/Abl-related Gene Stabilizes Actin Filaments, Stimulates Actin Branching by Actin-related Protein 2/3 Complex, and Promotes Actin Filament Severing by Cofilin

“…For example, Arg is present at 0.4 -0.6 M in dendritic spines, and cortactin concentrations may be as high as 4 M within breast cancer cell invadopodia (12,17,41). Dendritic spines in Arg-deficient neurons exhibit a loss of cortactin, reduced actin content, morphological changes, and loss of stability both in culture and in vivo (7,32). The cooperative binding of Arg and cortactin to actin filaments that we have described may help to concentrate Arg and cortactin binding to individual subsets of actin filaments (17)(18)(19) at levels sufficient to influence filament stability, branching, and severing in key subcellular compartments.…”

“…Arg and cortactin act together to mediate the formation, function, and stability of breast cancer cell invadopodia, fibroblast membrane ruffles, and cell edge protrusions and neuronal dendritic spines (8,16,32,42), processes that depend on actin filament networks. We present multiple mechanisms by which Arg stabilizes filaments in a cooperative manner with its substrate, cortactin, and promotes actin nucleation through increased branching and severing.…”

Erratum: Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction

“…Images were taken on a Joel 1220 TEM. PSD area was analyzed using ImageJ as previously described (21,37). Synaptic counts were taken at 2000 times magnification and clearly definable PSDs with presynaptic vesicles were counted as synapses.…”