ROCK/PKA Inhibition Rescues Hippocampal Hyperexcitability and GABAergic Neuron Alterations in a Oligophrenin-1 Knock-Out Mouse Model of X-Linked Intellectual Disability

Busti, Irene; Allegra, Manuela; Spalletti, Cristina; Panzi, Chiara; Restani, Laura; Billuart, Pierre; Caleo, Matteo

doi:10.1523/jneurosci.0462-19.2020

Cited by 13 publications

(9 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutations in the Rac1 RhoGEF DOCK4 disrupts dendritic spine dynamics and synaptic transmission, leading to ASD, schizophrenia, and dyslexia (Huang et al 2019; Xiao et al 2013; Guo et al 2019). Rac1 overactivation through loss of RhoGAPs can cause impaired dendritic development and cognition ( ARHGAP15 ) (Zamboni et al 2018a); X-linked intellectual disability ( OPHN1 ) (Busti et al 2020); and deficits in both axonal and dendritic development ( SRGAP s) (Fossati et al 2016; Perez, Sawmiller, and Tan 2016). Downstream of Rac1 in actin polymerization, mutations in PAK s and WASF1 can cause macrocephaly, seizures, intellectual disability, or ASD (Horn et al 2019; Ito et al 2018).…”

Section: Discussionmentioning

confidence: 99%

Comparing synaptic proteomes across seven mouse models for autism reveals molecular subtypes and deficits in Rho GTPase signaling

Freire-Cobo

Deyneko

et al. 2021

Preprint

View full text Add to dashboard Cite

Impaired synaptic function is a common phenotype in animal models for autism spectrum disorder (ASD), and ASD risk genes are enriched for synaptic function. Here we leverage the availability of multiple ASD mouse models exhibiting synaptic deficits and behavioral correlates of ASD and use quantitative mass spectrometry with isobaric tandem mass tagging (TMT) to compare the hippocampal synaptic proteomes from 7 mouse models. We identified common altered cellular and molecular pathways at the synapse, including changes in Rho family small GTPase signaling, suggesting that it may be a point of convergence in ASD. Comparative analyses also revealed clusters of synaptic profiles, with similarities observed among models for Fragile X syndrome (Fmr1 knockout), PTEN hamartoma tumor syndrome (Pten haploinsufficiency), and the BTBR+ model of idiopathic ASD. Opposing changes were found in models for cortical dysplasia focal epilepsy syndrome (Cntnap2 knockout), Phelan McDermid syndrome (Shank3 InsG3680), Timothy syndrome (Cacna1c G406R), and ANKS1B syndrome (Anks1b haploinsufficiency), which were similar to each other. We propose that these clusters of synaptic profiles form the basis for molecular subtypes that explain genetic heterogeneity in ASD despite a common clinical diagnosis. Drawn from an internally controlled survey of the synaptic proteome across animal models, our findings support the notion that synaptic dysfunction in the hippocampus is a shared mechanism of disease in ASD, and that Rho GTPase signaling may be an important pathway leading to disease phenotypes in autism.

show abstract

Section: Discussionmentioning

confidence: 99%

Comparing synaptic proteomes across seven mouse models for autism reveals molecular subtypes and deficits in Rho GTPase signaling

Freire-Cobo

Deyneko

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Ophn1 -KO mice recapitulate some aspects of the human phenotype, such as social, behavioral, and cognitive impairments, as well as ventricular enlargement and susceptibility to seizures [ 165 , 170 ]. At the cellular level, Ophn1 -KO mice show hyperexcitability of the hippocampal network, associated with a reduced number of hippocampal GABAergic interneurons, impaired dendritic spine maturation, and short-term synaptic plasticity [ 165 , 170 ]. Moreover, OPHN1 -deficient human iPSCs showed decreased neurogenic potential and impaired neurite elongation [ 171 ].…”

Section: Cytoskeleton Functions In Neuronal Developmentmentioning

confidence: 99%

“…A striking example of such a pharmacological treatment is provided by the Ophn1 -KO model of ID, which exhibits hyperactive RHOA signaling. In these mice, the administration of the ROCK/PKA inhibitor Fasudil rescued spine density, hippocampal hyperexcitability, ventricular enlargement, and behavioral abnormalities [ 170 , 429 ]. Fasudil was also able to rescue the decreased neurogenic potential and impaired neurite elongation in OPHN1-deficient human iPSCs [ 171 ].…”

Section: Therapeutic Opportunities For Cytoskeleton-related Forms Of Id and Related Conditionsmentioning

confidence: 99%

Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities

Liaci

Camera

Caslini

et al. 2021

IJMS

View full text Add to dashboard Cite

Intellectual disability (ID) is a pathological condition characterized by limited intellectual functioning and adaptive behaviors. It affects 1–3% of the worldwide population, and no pharmacological therapies are currently available. More than 1000 genes have been found mutated in ID patients pointing out that, despite the common phenotype, the genetic bases are highly heterogeneous and apparently unrelated. Bibliomic analysis reveals that ID genes converge onto a few biological modules, including cytoskeleton dynamics, whose regulation depends on Rho GTPases transduction. Genetic variants exert their effects at different levels in a hierarchical arrangement, starting from the molecular level and moving toward higher levels of organization, i.e., cell compartment and functions, circuits, cognition, and behavior. Thus, cytoskeleton alterations that have an impact on cell processes such as neuronal migration, neuritogenesis, and synaptic plasticity rebound on the overall establishment of an effective network and consequently on the cognitive phenotype. Systems biology (SB) approaches are more focused on the overall interconnected network rather than on individual genes, thus encouraging the design of therapies that aim to correct common dysregulated biological processes. This review summarizes current knowledge about cytoskeleton control in neurons and its relevance for the ID pathogenesis, exploiting in silico modeling and translating the implications of those findings into biomedical research.

show abstract

“…In PV-ChR2 mice, we assessed colocalization of mCherry-ChR2 and parvalbumin. While mCherry staining was detectable in coronal sections without any amplification step, parvalbumin immunolabelling was performed with a primary guinea pig polyclonal antibody (1:500; SySy, Germany) as described (Busti et al, 2020). Counts of double labelled cells were performed using Neurolucida software (Allegra et al, 2017).…”

Section: Immunohistochemical Analysismentioning

confidence: 99%

Differential roles of pyramidal and fast-spiking, GABAergic neurons in the control of glioma cell proliferation

Tantillo

Vannini

Cerri

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

AbstractRecent studies have demonstrated an active role for neurons in glioma progression. Specifically, peritumoral neurons establish functional excitatory synapses with glioma cells, and optogenetic stimulation of cortical pyramidal neurons drives tumor progression. However, the specific role of different subsets of cortical neurons, such as GABAergic interneurons, remains unexplored. Here, we directly compared the effects of optogenetic stimulation of pyramidal cells vs. fast-spiking, GABAergic neurons. In mice inoculated with GL261 cells into the motor cortex, we show that optogenetic stimulation of pyramidal neurons enhances glioma cell proliferation. In contrast, optogenetic stimulation of fast-spiking, parvalbumin-positive interneurons reduces proliferation as measured by BrdU incorporation and Ki67 immunolabelling. Since both principal cells and fast-spiking interneurons are directly activated by sensory afferent input, we next placed tumors in the occipital cortex to test the impact of visual stimulation/deprivation. We report that total lack of visual input via dark rearing enhances the density of proliferating glioma cells, while daily visual stimulation by gratings of different spatial frequencies and contrast reduces tumor growth. The effects of sensory input are region-specific, as visual deprivation has no significant effect on tumor proliferation in mice with gliomas in the motor cortex. We also report that sensory stimulation combined with temozolomide administration delays the loss of visual responses in peritumoral neurons. Altogether, these data demonstrate complex effects of different neuronal subtypes in the control of glioma proliferation.HighlightsActivity of GABAergic neurons reduces glioma cell proliferationLevels of sensory afferent input regulate tumor proliferationEffects of sensory input are region-specific

show abstract

ROCK/PKA Inhibition Rescues Hippocampal Hyperexcitability and GABAergic Neuron Alterations in a Oligophrenin-1 Knock-Out Mouse Model of X-Linked Intellectual Disability

Abstract: We thank Francesca Biondi (CNR Pisa) for animal care and Elena Novelli (CNR Pisa) for microscopy technical support. This work was funded by Telethon Foundation (project #GGP11116 to M.C.) and by Fondazione Cassa di Risparmio di Padova e Rovigo (Foundation Cariparo, project #52000 to M.C.).

Cited by 13 publications

References 59 publications

Comparing synaptic proteomes across seven mouse models for autism reveals molecular subtypes and deficits in Rho GTPase signaling

Comparing synaptic proteomes across seven mouse models for autism reveals molecular subtypes and deficits in Rho GTPase signaling

Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities

Differential roles of pyramidal and fast-spiking, GABAergic neurons in the control of glioma cell proliferation

Contact Info

Product

Resources

About