Enhancement of learning and memory after activation of cerebral Rho GTPases

Diana, Giovanni; Valentini, G.; Travaglione, Sara; Falzano, Loredana; Pieri, Massimo; Zona, Cristina; Meschini, Stefania; Fabbri, Alessia; Fiorentini, Carla

doi:10.1073/pnas.0610059104

Cited by 118 publications

(133 citation statements)

References 54 publications

(63 reference statements)

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“…Rats that were injected in the intra-dorsal hippocampus with the Rac1 inhibitor NSC23766 prior to conditioned pairing exhibited a strong CPA, demonstrating that RhoA, but not Rac1, was required in aversive memory acquisition. This result is in accordance with a previous study showing that genetic disruption or pharmacological inactivation of the RhoA-ROCK signaling pathway in the hippocampus impaired long-term learning and memory in rats [44] .…”

Section: Discussionsupporting

confidence: 83%

“…They oscillate between a GTP-bound active state and a GDP-bound inactive state and act as molecular switches that control the organization and dynamics of the actin cytoskeleton [18] . Much evidence has demonstrated that the Rho GTPases control the assembly and disassembly of the actin cytoskeleton and regulate actin rearrangements at synapses in response to extracellular signals [19,20] . These findings suggest the possibility that the Rho GTPases may be involved in synaptic actin polymerization.…”

Section: Introductionmentioning

confidence: 99%

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The small GTPase RhoA, but not Rac1, is essential for conditioned aversive memory formation through regulation of actin rearrangements in rat dorsal hippocampus

Wang

Hou

et al. 2013

Acta Pharmacol Sin

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Aim: Actin rearrangements are induced in the dorsal hippocampus after conditioned morphine withdrawal, and involved in the formation of conditioned place aversion. In the present study, we investigated the mechanisms underlying the actin rearrangements in rat dorsal hippocampus induced by conditioned morphine withdrawal. Methods: The RhoA-ROCK pathway inhibitor Y27632 (8.56 μg/1 μL per side) or the Rac1 inhibitor NSC23766 (25 μg/1 μL per side) was microinjected into the dorsal hippocampus of rats. Conditioned place aversion (CPA) induced by naloxone-precipitated morphine withdrawal was assessed. Crude synaptosomal fraction of hippocampus was prepared, and the amount of F-actin and G-actin was measured with an Actin Polymerization Assay Kit. Results: Conditioned morphine withdrawal significantly increased actin polymerization in the dorsal hippocampus at 1 h following the naloxone injection. Preconditioning with microinjection of Y27632, but not NSC23766, attenuated CPA, and blocked the increase in actin polymerization in the dorsal hippocampus. Conclusion: Our results suggest that the small GTPase RhoA, but not Rac1, in the dorsal hippocampus is responsible for CPA formation, mainly through its regulation of actin rearrangements.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

The small GTPase RhoA, but not Rac1, is essential for conditioned aversive memory formation through regulation of actin rearrangements in rat dorsal hippocampus

Wang

Hou

et al. 2013

Acta Pharmacol Sin

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“…Local injection of CNF1 has been shown to increase dendritic spine density in the rat visual cortex [41]. More importantly, these newly formed dendritic spines appear to be functional, as intracerebroventricular (ICV) injection of CNF1 can persistently (up to 90 days post-treatment) increase hippocampal neurotransmission, long-term potentiation (LTP), and memory in wild-type mice [42][43][44]. These benefits may also translate to other neurological disorders.…”

Section: Direct Modulation Of Rho-gtpases For Ad Treatmentmentioning

confidence: 99%

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

Lefort

2015

Neurotherapeutics

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Alzheimer's disease (AD) is a monumental public health crisis with no effective cure or treatment. To date, therapeutic strategies have focused almost exclusively on upstream signaling events in the disease, namely on β-amyloid and amyloid precursor protein processing, and have, unfortunately, yielded few, if any, promising results. An alternative approach may be to target signaling events downstream of β-amyloid and even tau. However, with so many pathways already linked to the disease, understanding which ones are "drivers" versus "passengers" in the pathogenesis of the disease remains a tremendous challenge. Given the critical roles of Rho-guanosine triphosphatases (GTPases) in regulating the actin cytoskeleton and spine dynamics, and the strong association between spine abnormalities and cognition, it is not surprising that mutations in a number of genes involved in RhoGTPase signaling have been implicated in several brain disorders, including schizophrenia and autism. And now, there is mounting literature implicating Rho-GTPase signaling in AD pathogenesis as well. Here, I review this evidence, with a particular emphasis on the regulators of Rho-GTPase signaling, namely guanine nucleotide exchange factors and GTPaseactivating proteins. Several of these have been linked to various aspects of AD, and each offers a novel potential therapeutic target for AD.

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“…Rho GTPases can be blocked in their activated, GTP-bound state by a bacterial protein toxin from Escherichia coli, named cytotoxic necrotizing factor 1 (CNF1). CNF1 catalyzes the deamidation of a single glutamine residue of the Rho molecules, thus impeding GTP hydrolysis and leading to their persistent activation (Flatau et al, 1997;Schmidt et al, 1997;Diana et al, 2007). Here we have exploited this enzymatic activity to examine whether stimulation of structural rearrangements reinstates experience-dependent plasticity in adult age.…”

Section: Introductionmentioning

confidence: 99%

Activation of Rho GTPases Triggers Structural Remodeling and Functional Plasticity in the Adult Rat Visual Cortex

Cerri¹,

Fabbri²,

Vannini³

et al. 2011

J. Neurosci.

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A classical example of age-dependent plasticity is ocular dominance (OD) plasticity, triggered by monocular deprivation (MD). Sensitivity of cortical circuits to a brief period of MD is maximal in juvenile animals and downregulated in adult age. It remains unclear whether a reduced potential for morphological remodeling underlies this downregulation of physiological plasticity in adulthood. Here we have tested whether stimulation of structural rearrangements is effective in promoting experience-dependent plasticity in adult age. We have exploited a bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1), that regulates actin dynamics and structure of neuronal processes via a persistent activation of Rho GTPases. Injection of CNF1 into the adult rat visual cortex triggered a long-lasting activation of the Rho GTPase Rac1, with a consequent increase in spine density and length in pyramidal neurons. Adult rats treated with CNF1, but not controls, showed an OD shift toward the open eye after MD. CNF1-mediated OD plasticity was selectively attributable to the enhancement of open-eye responses, whereas closed-eye inputs were unaffected. This effect correlated with an increased density of geniculocortical terminals in layer IV of monocularly deprived, CNF1-treated rats. Thus, Rho GTPase activation reinstates OD plasticity in the adult cortex via the potentiation of more active inputs from the open eye. These data establish a direct link between structural remodeling and functional plasticity and demonstrate a role for Rho GTPases in brain plasticity in vivo. The plasticizing effects of Rho GTPase activation may be exploited to promote brain repair.

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Enhancement of learning and memory after activation of cerebral Rho GTPases

Cited by 118 publications

References 54 publications

The small GTPase RhoA, but not Rac1, is essential for conditioned aversive memory formation through regulation of actin rearrangements in rat dorsal hippocampus

The small GTPase RhoA, but not Rac1, is essential for conditioned aversive memory formation through regulation of actin rearrangements in rat dorsal hippocampus

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

Activation of Rho GTPases Triggers Structural Remodeling and Functional Plasticity in the Adult Rat Visual Cortex

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