The dendritic tree and brain disorders

Kulkarni, Vaishali A.; Firestein, Bonnie L.

doi:10.1016/j.mcn.2012.03.005

Cited by 350 publications

(315 citation statements)

References 226 publications

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“…These changes caused a thinning of anatomical layers in the cortex and hippocampus in adult mice, as it has been reported that dendrite disruption and reduced dendritic arbor complexity determine brain size in adult animals (16). Furthermore, the reduction in dendritic spine density and synapses altered synaptic connectivity that, in the hippocampus, likely contributed to the anxiety and impaired learning, cognition, and memory phenotypes that recapitulate the alterations seen in a variety of psychiatric and neurodegenerative disorders (2,3). Thus, APC/C Cdh1 maintains structural and functional integrity of dendritic networks, suggesting that Cdh1 is important for the molecular pathogenesis of memory disorders.…”

Section: Discussionmentioning

confidence: 86%

“…Loss of dendrite stability is associated with psychiatric disorders and neurodegenerative diseases. Dendritic disruption and loss of dendritic spines and synapses have been reported in schizophrenia and depression, as well as in neurodegenerative conditions, including Alzheimer's disease (AD), and after an excitotoxic insult during stroke (2,3). The serinethreonine Rho protein kinase (Rock), an effector of the RhoA GTPase (4), is a central regulator of the microtubule cytoskeleton in neurons.…”

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confidence: 99%

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APC/C ^Cdh1 -Rock2 pathway controls dendritic integrity and memory

Bobo-Jiménez

Delgado‐Esteban

Angibaud

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Disruption of neuronal morphology contributes to the pathology of neurodegenerative disorders such as Alzheimer's disease (AD). However, the underlying molecular mechanisms are unknown. Here, we show that postnatal deletion of Cdh1, a cofactor of the anaphasepromoting complex/cyclosome (APC/C) ubiquitin ligase in neurons [Cdh1 conditional knockout (cKO)], disrupts dendrite arborization and causes dendritic spine and synapse loss in the cortex and hippocampus, concomitant with memory impairment and neurodegeneration, in adult mice. We found that the dendrite destabilizer Rho protein kinase 2 (Rock2), which accumulates in the brain of AD patients, is an APC/C Cdh1 substrate in vivo and that Rock2 protein and activity increased in the cortex and hippocampus of Cdh1 cKO mice. In these animals, inhibition of Rock activity, using the clinically approved drug fasudil, prevented dendritic network disorganization, memory loss, and neurodegeneration. Thus, APC/C Cdh1 -mediated degradation of Rock2 maintains the dendritic network, memory formation, and neuronal survival, suggesting that pharmacological inhibition of aberrantly accumulated Rock2 may be a suitable therapeutic strategy against neurodegeneration.APC/C Cdh1 | Rock | dendrite | memory | neurodegeneration

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Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

APC/C ^Cdh1 -Rock2 pathway controls dendritic integrity and memory

Bobo-Jiménez

Delgado‐Esteban

Angibaud

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In humans dendrite abnormalities are associated with a range of developmental neurological disorders, several of which are caused by mutations in microtubule regulators 1,2,45,46 . Mutations in CDK5RAP2…”

Section: Discussionmentioning

confidence: 99%

“…It enables the neuron to properly cover its receptive field and establishes the positions of inputs into the arbor. Disruptions in dendritic branching can precipitate intellectual disability and psychiatric disorders 1,2 . Arbor morphology is regulated for each neuron class to support its structural and functional requirements 3 .…”

mentioning

confidence: 99%

Centrosomin represses dendrite branching by orienting microtubule nucleation

et al. 2015

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“…1,2 Alterations in arbor patterning occur in multiple neuropsychiatric and neurological disorders including intellectual disability syndromes, autism spectrum disorders, schizophrenia, and neurodegenerative diseases. 3 A nascent neuron has a simple morphology and must undergo a complex differentiation process to create a highly branched dendrite arbor. 4 Moreover, as beautifully illustrated more than 125 years ago by Ramon y Cajal, 5 the dendrite differentiation process must be organized in order to create arbor morphologies that fit the specific functional requirements of that neuron type.…”

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confidence: 99%