0
Get Alert
Please Wait... Processing your request... Please Wait.
You must sign in to sign-up for alerts.

Please confirm that your email address is correct, so you can successfully receive this alert.

1
Letter to the Editor   |    
Reduced Spinophilin in Schizophrenia
ANDREW J. DWORK, M.D.; GORAZD ROSOKLIJA, M.D., Ph.D.; LIESL B. JONES, Ph.D.
Am J Psychiatry 2005;162:1389-1389. doi:10.1176/appi.ajp.162.7.1389

To the Editor: Amanda J. Law, Ph.D., et al. (1) reported decreased mRNA for spinophilin in the hippocampal formation in patients with schizophrenia and mood disorders. The potential implications of this abnormality are curious since spinophilin is involved in limiting or decreasing the length of dendritic spines. Spinophilin immunoreactivity is predominantly (although not exclusively) localized to dendritic spines (2), for which it is a meaningful marker, with hippocampal spine density and spinophilin immunoreactivity both increasing in response to estrogen (3). However, spinophilin is not necessary for the formation of spines, which are increased in density in young spinophilin knockout mice or for their removal, since spine density returns to normal when such animals mature (4).

Spinophilin links protein phosphatase-1 to actin. Dephosphorylation of actin by protein phosphatase-1 leads to its disassembly (5), so the targeting of protein phosphatase-1 to actin is likely to result in fewer or shorter dendritic spines. Linking protein phosphatase-1 to actin also promotes dephosphorylation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (4). The subsequent decrease in the activity of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors should decrease calcium influx into the spine, reducing the phosphorylation of spinophilin by calcium-calmodulin kinase II and thereby enhancing its affinity for actin (6).

The reported subicular decrease in spinophilin mRNA in schizophrenia is approximately 30% (1). We observed a decrease of 75%–80% in the density of apical dendritic spines (plus a more modest decrease in apical dendritic arborization) (7), but the density of spines on basilar dendrites has not been measured. If the diminished pool of mRNA is supporting the synthesis of spinophilin for an even more diminished set of dendritic spines, increased synthesis of spinophilin, on a per-spine basis, might function to keep spine density reduced. Posttranscriptional mechanisms are also likely, as evidenced by estrogen-induced increases in spine density and spinophilin immunoreactivity, without altered levels of spinophilin mRNA (3).

Law AJ, Weickert CS, Hyde TM, Kleinman JE, Harrison PJ: Reduced spinophilin but not microtubule-associated protein 2 expression in the hippocampal formation in schizophrenia and mood disorders: molecular evidence for a pathology of dendritic spines. Am J Psychiatry  2004; 161:1848–1855
[PubMed]
[CrossRef]
 
Muly EC, Smith Y, Allen P, Greengard P: Subcellular distribution of spinophilin immunolabeling in primate prefrontal cortex: localization to and within dendritic spines. J Comp Neurol  2004; 469:185–197
[PubMed]
[CrossRef]
 
Lee SJ, Romeo RD, Svenningsson P, Campomanes CR, Allen PB, Greengard P, McEwen BS: Estradiol affects spinophilin protein differently in gonadectomized males and females. Neuroscience  2004; 127:983–988
[PubMed]
[CrossRef]
 
Feng J, Yan Z, Ferreira A, Tomizawa K, Liauw JA, Zhuo M, Allen PB, Ouimet CC, Greengard P: Spinophilin regulates the formation and function of dendritic spines. Proc Natl Acad Sci USA  2000; 97:9287–9292
[PubMed]
[CrossRef]
 
Fernandez A, Brautigan DL, Mumby M, Lamb NJ: Protein phosphatase type-1, not type-2A, modulates actin microfilament integrity and myosin light chain phosphorylation in living nonmuscle cells. J Cell Biol  1990; 111:103–112
[PubMed]
[CrossRef]
 
Grossman SD, Futter M, Snyder GL, Allen PB, Nairn AC, Greengard P, Hsieh-Wilson LC: Spinophilin is phosphorylated by Ca2+/calmodulin-dependent protein kinase II resulting in regulation of its binding to F-actin. J Neurochem  2004; 90:317–324
[PubMed]
[CrossRef]
 
Rosoklija G, Toomayan G, Ellis SP, Keilp J, Mann JJ, Latov N, Hays AP, Dwork AJ: Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders: preliminary findings. Arch Gen Psychiatry  2000; 57:349–356
[PubMed]
[CrossRef]
 
+

References

Law AJ, Weickert CS, Hyde TM, Kleinman JE, Harrison PJ: Reduced spinophilin but not microtubule-associated protein 2 expression in the hippocampal formation in schizophrenia and mood disorders: molecular evidence for a pathology of dendritic spines. Am J Psychiatry  2004; 161:1848–1855
[PubMed]
[CrossRef]
 
Muly EC, Smith Y, Allen P, Greengard P: Subcellular distribution of spinophilin immunolabeling in primate prefrontal cortex: localization to and within dendritic spines. J Comp Neurol  2004; 469:185–197
[PubMed]
[CrossRef]
 
Lee SJ, Romeo RD, Svenningsson P, Campomanes CR, Allen PB, Greengard P, McEwen BS: Estradiol affects spinophilin protein differently in gonadectomized males and females. Neuroscience  2004; 127:983–988
[PubMed]
[CrossRef]
 
Feng J, Yan Z, Ferreira A, Tomizawa K, Liauw JA, Zhuo M, Allen PB, Ouimet CC, Greengard P: Spinophilin regulates the formation and function of dendritic spines. Proc Natl Acad Sci USA  2000; 97:9287–9292
[PubMed]
[CrossRef]
 
Fernandez A, Brautigan DL, Mumby M, Lamb NJ: Protein phosphatase type-1, not type-2A, modulates actin microfilament integrity and myosin light chain phosphorylation in living nonmuscle cells. J Cell Biol  1990; 111:103–112
[PubMed]
[CrossRef]
 
Grossman SD, Futter M, Snyder GL, Allen PB, Nairn AC, Greengard P, Hsieh-Wilson LC: Spinophilin is phosphorylated by Ca2+/calmodulin-dependent protein kinase II resulting in regulation of its binding to F-actin. J Neurochem  2004; 90:317–324
[PubMed]
[CrossRef]
 
Rosoklija G, Toomayan G, Ellis SP, Keilp J, Mann JJ, Latov N, Hays AP, Dwork AJ: Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders: preliminary findings. Arch Gen Psychiatry  2000; 57:349–356
[PubMed]
[CrossRef]
 
+
+

CME Activity

There is currently no quiz available for this resource. Please click here to go to the CME page to find another.
Submit a Comments
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discertion of APA editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe



Related Content
Books
Manual of Clinical Psychopharmacology, 7th Edition > Chapter 1.  >
Manual of Clinical Psychopharmacology, 7th Edition > Chapter 2.  >
Manual of Clinical Psychopharmacology, 7th Edition > Chapter 9.  >
The American Psychiatric Publishing Textbook of Psychiatry, 5th Edition > Chapter 6.  >
The American Psychiatric Publishing Textbook of Psychiatry, 5th Edition > Chapter 10.  >
Topic Collections
Psychiatric News
Read more at Psychiatric News >>
APA Guidelines
PubMed Articles