Activity-Independent Regulation of Dendrite Patterning by Postsynaptic Density Protein PSD-95

Charych, Erik I.; Akum, Barbara F.; Goldberg, Joshua S.; Jörnsten, Rebecka; Rongo, Christopher; Zheng, James; Firestein, Bonnie L.

doi:10.1523/jneurosci.2379-06.2006

Cited by 135 publications

(173 citation statements)

References 55 publications

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“…Previous studies have shown that PSD-95 contributes to the processes of dendrite development, spine formation, and spine maturation (38). Furthermore, the involvement of PSD-95 in dendritic spine maturation and clustering of synaptic signaling proteins indicates the critical role this protein has in regulating dendritic outgrowth and branching (39). Although the precise impact of irradiation on these processes is relatively unknown, past work has shown that in immature neurons, overexpression of PSD-95 decreases the proportion of primary dendrites that undergo additional branching, resulting in marked reductions of secondary dendrites (39).…”

Section: Discussionmentioning

confidence: 99%

Cranial irradiation compromises neuronal architecture in the hippocampus

Parihar

Limoli

2013

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

194

199

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Cranial irradiation is used routinely for the treatment of nearly all brain tumors, but may lead to progressive and debilitating impairments of cognitive function. Changes in synaptic plasticity underlie many neurodegenerative conditions that correlate to specific structural alterations in neurons that are believed to be morphologic determinants of learning and memory. To determine whether changes in dendritic architecture might underlie the neurocognitive sequelae found after irradiation, we investigated the impact of cranial irradiation (1 and 10 Gy) on a range of micromorphometric parameters in mice 10 and 30 d following exposure. Our data revealed significant reductions in dendritic complexity, where dendritic branching, length, and area were routinely reduced (>50%) in a dose-dependent manner. At these same doses and times we found significant reductions in the number (20-35%) and density (40-70%) of dendritic spines on hippocampal neurons of the dentate gyrus. Interestingly, immature filopodia showed the greatest sensitivity to irradiation compared with more mature spine morphologies, with reductions of 43% and 73% found 30 d after 1 and 10 Gy, respectively. Analysis of granule-cell neurons spanning the subfields of the dentate gyrus revealed significant reductions in synaptophysin expression at presynaptic sites in the dentate hilus, and significant increases in postsynaptic density protein (PSD-95) were found along dendrites in the granule cell and molecular layers. These findings are unique in demonstrating dose-responsive changes in dendritic complexity, synaptic protein levels, spine density and morphology, alterations induced in hippocampal neurons by irradiation that persist for at least 1 mo, and that resemble similar types of changes found in many neurodegenerative conditions. radiation-induced cognitive dysfunction | radiation injury | structural plasticity

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Section: Discussionmentioning

confidence: 99%

Cranial irradiation compromises neuronal architecture in the hippocampus

Parihar

Limoli

2013

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

194

199

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“…), neurons were transfected using the Effectene reagent (QIAGEN, Valencia, CA) as is done routinely in our laboratory. 3,4,15 Cultures were allowed to express the transfected proteins for 48 h. Images of transfected hippocampal neurons were taken as described previously, 4 and neurons were confirmed by MAP2 immunostaining. Primary and secondary dendrites were counted as previously described.…”

Section: Neuronal Culture Transfection and Dendrite Branching Numbementioning

confidence: 99%

“…Primary and secondary dendrites were counted as previously described. 3,4,15 To acquire unbiased dendrite number counts, the analyzing person was blinded to the transfection condition.…”

Section: Neuronal Culture Transfection and Dendrite Branching Numbementioning

confidence: 99%

Structural characterization of the zinc binding domain in cytosolic PSD‐95 interactor (cypin): Role of zinc binding in guanine deamination and dendrite branching

Fernández

Welsh²,

Firestein

2008

Proteins

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Dendrite morphology regulates how a postsynaptic neuron receives information from presynaptic neurons. The specific patterning of dendrite branches is promoted by extrinsic and intrinsic factors that trigger the activation of functional signaling pathways. However, most of the regulating factors and the biochemical mechanisms involved in regulating dendrite branching are unknown. Our laboratory previously reported that cypin (cytosolic PSD-95 interactor) plays an active role in regulating dendrite branching in hippocampal neurons. Cypin-promoted increases in dendrite number are dependent on guanine deaminase activity. In order to identify the specific structural role of zincbinding in cypin-mediated dendrite branching and guanine deaminase activity, we employed computational homology modeling techniques to construct a three dimensional structural model of cypin. Analysis of the protein-ion sequestration scaffold of this model identified several histidines and aspartic acid residues responsible for zinc binding. Single substitution mutations in these specific sites completely disrupted the guanine deaminase enzymatic activity and rendered cypin unable to promote dendrite branching in rat hippocampal neurons. The specific zinc ion-binding function of each residue in the protein scaffold was also confirmed by Inductively Coupled Plasma-Optic Emission Spectrometry. Inspection of our structural model confirmed that His82 and His84 coordinate with the zinc ion, together with His240, His279, and Asp330, residues that until now were unknown to play a role in this regard. Furthermore, promotion of dendrite branching by cypin is zincdependent.

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“…We previously reported that PSD-95 decreases dendrite branching by disrupting microtubule organization (Charych et al, 2006;Sweet et al, 2011a,b). Moreover, PSD-95 is in a complex with F-actin, and PSD-95 overexpression enhances dendritic spine formation and stabilization (Okabe et al, 1999;El-Husseini et al, 2000;Horne and Dell'Acqua, 2007).…”

Section: Introductionmentioning

confidence: 97%

“…Moreover, PSD-95 is in a complex with F-actin, and PSD-95 overexpression enhances dendritic spine formation and stabilization (Okabe et al, 1999;El-Husseini et al, 2000;Horne and Dell'Acqua, 2007). Cypin increases dendrite branching by promoting microtubule polymerization and negatively regulating PSD-95 clustering (Firestein et al, 1999;Akum et al, 2004;Charych et al, 2006). Accordingly, cypin and PSD-95 may be involved in the machinery that maintains dendrite integrity and promotes spine retraction and reemergence in response to sublethal glutamate exposure.…”

Section: Introductionmentioning

confidence: 99%

The Role of PSD-95 and Cypin in Morphological Changes in Dendrites Following Sublethal NMDA Exposure

Tseng¹,

Firestein²

2011

J. Neurosci.

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Focal swelling or varicosity formation in dendrites and loss of dendritic spines are the earliest indications of glutamate-induced excitotoxicity. Although it is known that microtubule dynamics play a role in varicosity formation, very little is known about the proteins that directly impact microtubules during focal swelling and dendritic spine loss. Our laboratory has recently reported that the postsynaptic protein PSD-95 and its cytosolic interactor (cypin) regulate the patterning of dendrites in hippocampal neurons. Cypin promotes microtubule assembly, and PSD-95 disrupts microtubule organization. Thus, we hypothesized that cypin and PSD-95 may play a role in altering dendrite morphology and spine number in response to sublethal NMDA-induced excitotoxicity. Using an in vitro model of glutamateinduced toxicity in rat hippocampal cultures, we found that cypin overexpression or PSD-95 knockdown increases the percentage of neurons with varicosities and the number of varicosities along dendrites, decreases the size of varicosities after sublethal NMDA exposure, and protects neurons from NMDA-induced death. In contrast, cypin knockdown or PSD-95 overexpression results in opposite effects. We further show that cypin regulates the density of spines/filopodia: cypin overexpression decreases the number of protrusions per micrometer of dendrite while cypin knockdown results in an opposite effect. Cypin overexpression and PSD-95 knockdown attenuate NMDA-promoted decreases in protrusion density. Thus, we have identified a novel pathway by which the microtubule cytoskeleton is regulated during sublethal changes to dendrites.

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Activity-Independent Regulation of Dendrite Patterning by Postsynaptic Density Protein PSD-95

Cited by 135 publications

References 55 publications

Cranial irradiation compromises neuronal architecture in the hippocampus

Cranial irradiation compromises neuronal architecture in the hippocampus

Structural characterization of the zinc binding domain in cytosolic PSD‐95 interactor (cypin): Role of zinc binding in guanine deamination and dendrite branching

The Role of PSD-95 and Cypin in Morphological Changes in Dendrites Following Sublethal NMDA Exposure

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